Amide derivatives as FLT-3 modulators

ABSTRACT

The invention provides methods and compositions for treating conditions mediated by flt-3 wherein derivatives of amide compounds are employed. The invention also provides methods of using the compounds and/or compositions in the treatment of a variety of diseases and unwanted conditions in subjects.

This application claims priority to U.S. Provisional Application No.60/520,273, filed Nov. 13, 2003, U.S. Provisional Application No.60/527,094, filed Dec. 3, 2003, U.S. Provisional Application No.60/531,243, filed Dec. 18, 2003, and U.S. Provisional Application No.60/531,082, filed Dec. 18, 2003, the contents of which are incorporatedherein by reference in their entirety.

BACKGROUND

Protein kinases (PKs) play a role in signal transduction pathwaysregulating a number of cellular functions, such as cell growth,differentiation, and cell death. PKs are enzymes that catalyze thephosphorylation of hydroxy groups on tyrosine, serine and threonineresidues of proteins, and can be conveniently broken down into twoclasses, the protein tyrosine kinases (PTKs) and the serine-threoninekinases (STKs). Growth factor receptors with PTK activity are known asreceptor tyrosine kinases. Protein receptor tyrosine kinases are afamily of tightly regulated enzymes, and the aberrant activation ofvarious members of the family is one of the hallmarks of cancer. Theprotein-tyrosine kinase family, which includes Bcr-Abl tyrosine kinase,can be divided into subgroups that have similar structural organizationand sequence similarity within the kinase domain. The members of thetype III group of receptor tyrosine kinases include the platelet-derivedgrowth factor (PDGF) receptors (PDGF receptors α and β),colony-stimulating factor (CSF-1) receptor (CSF-1R, c-Fms), FLT-3, andstem cell or steel factor receptor (c-kit). A more complete listing ofthe known Protein receptor tyrosine kinases subfamilies is described inPlowman et al., DN&P, 7(6):334-339 (1994), which is incorporated byreference, including any drawings, as if fully set forth herein.Furthermore, for a more detailed discussion of “non-receptor tyrosinekinases”, see Bolen, Oncogene, 8:2025-2031 (1993), which is incorporatedby reference, including any drawings, as if fully set forth herein.

Hematologic cancers, also known as hematologic or hematopoieticmalignancies, are cancers of the blood or bone marrow; includingleukemia and lymphoma. Acute myelogenous leukemia (AML) is a clonalhematopoietic stem cell leukemia that represents ˜90% of all acuteleukemias in adults. See e.g., Lowenberg et al., N. Eng. J. Med.341:1051-62 (1999). While chemotherapy can result in completeremissions, the long term disease-free survival rate for AML is about14% with about 7,400 deaths from AML each year in the United States. Thesingle most commonly mutated gene in AML is FLT3 kinase. See e.g.,Abu-Duhier et al., Br. J. Haemotol. 111:190-05 (2000); Kiyoi et al.,Blood 93:3074-80 (1999); Kottaridis et al., Blood 98:1752-59 (2001);Stirewalt et al., Blood 97:3589-95 (2001). Such mutations also indicatea poor prognosis for the patient.

The compounds provided by the present invention are urea derivatives ofsubstituted aryls and hetroaryls, e.g., isoxazoles, pyrazoles andisothiazoles. Urea derivatives of pyrazoles have been reported to beselective p38 kinase inhibitors by Dumas, J., et al., Bioorg. Medic.Chem. Lett. 10:2051-2054 (2000). Oxazoles and isopyrazoles are suggestedas blockers of cytokine production in WO 00/43384 published 27 Jul.2000. Urea derivatives of isoxazole and pyrazoles are described asinhibitors of RAF kinase in WO 99/32106 published 1 Jul. 1999. Suchcompounds are also described as p38 kinase inhibitors by Dumas, J., etal., Bioorg. Medic. Chem. Lett. 10:2047-2050 (2000). These compounds arealso suggested as p38 kinase inhibitors in PCT publication WO 99/32111published 1 Jul. 1999.

There remains a need for additional compounds that are effective ininhibiting kinase activity. Given the complexities of signaltransduction with the redundancy and crosstalk between various pathways,the identification of specific kinase inhibitors permits accuratetargeting with limited inhibition of other pathways, thus reducing thetoxicity of such inhibitory compounds.

SUMMARY OF THE INVENTION

The present invention provides compounds which modulate kinase activity,and in some embodiments inhibit protein tyrosine kinases or a specifickinase or kinase class. In some embodiments, the compositions andmethods for treating and preventing conditions and diseases, such ascancer, hematologic malignancies, cardiovascular disease, inflammationor multiple sclerosis. The compounds of the invention can be deliveredalone or in combination with additional agents, and are used for thetreatment and/or prevention of conditions and diseases. Unless otherwisestated, each of the substituents is as previously defined.

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

wherein:

-   -   (a) A_(a1) is N—R_(3a) or C—R_((3a)2) and A_(a2) is N—R_(3a) or        C—R_((3a)2), wherein one of A_(a1) or A_(a2) is N and one is C        wherein each R_(3a) is independently a suitable substituent        selected from hydrogen, or an alkyl, alkenyl, heteroalkyl,        haloalkyl, alkynyl, aryl, cycloalkyl, heterocycloalkyl,        heteroaryl group unsubstituted or substituted with one or more        suitable substituents independently selected from the group        consisting of: halogens; —CN; and —NO₂; and alkyl, alkenyl,        heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl,        heterocycloalkyl, heteroaryl, —(CH₂)_(z)CN where z is a whole        integer, preferably from 0 to 4, ═NH, —NHOH, —OH, —C(O)H,        —OC(O)H, —C(O)OH, —OC(O)OH, —OC(O)OC(O)H, —OOH, —C(NH)NH₂,        —NHC(NH)NH₂, —C(S)NH₂, —NHC(S)NH₂, —NHC(O)NH₂, —S(O₂)H, —S(O)H,        —NH₂, —C(O)NH₂, —OC(O)NH₂, —NHC(O)H, —NHC(O)OH,—C(O)NHC(O)H,        —OS(O₂)H, —OS(O)H, —OSH, —SC(O)H, —S(O)C(O)OH, —SO₂C(O)OH,        —NHSH, —NHS(O)H, —NHSO₂H, —C(O)SH, —C(O)S(O)H, —C(O)S(O₂)H,        —C(S)H, —C(S)OH, —C(SO)OH, —C(SO₂)OH, —NHC(S)H, —OC(S)H,        —OC(S)OH, —OC(SO₂)H, —S(O₂)NH₂, —S(O)NH₂, —SNH₂, —NHCS(O₂)H,        —NHC(SO)H, —NHC(S)H, and —SH groups unsubstituted or substituted        with one or more suitable substituents independently selected        from the group consisting of halogens, ═O, —NO₂, —CN,        —(CH₂)_(z)—CN where z is a whole integer, preferably from 0 to        4, —OR_(c), —NR_(c)OR_(c), —NR_(c)R_(c),—C(O)NR_(c),        —C(O)OR_(c), —C(O)R_(c),        —NR_(c)C(O)NR_(c)R_(c),—NR_(c)C(O)R_(c), —OC(O)OR_(c),        —OC(O)NR_(c)R_(c), —SR_(c), unsubstituted alkyl, unsubstituted        alkenyl, unsubstituted alkynyl, unsubstituted aryl,        unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and        unsubstituted heteroaryl, or two or more substituents cyclize to        form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl,        aryl, or heteroaryl group, where each R_(c) is indepenently        selected from hydrogen, unsubstituted alkyl, unsubstituted        alkenyl, unsubstituted alkynyl, unsubstituted aryl,        unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and        unsubstituted heteroaryl, or two or more R_(c) groups together        cyclize to form part of a heteroaryl or heterocycloalkyl group        unsubstituted or substituted with an unsubstituted alkyl group;        or two R_(3a's) cyclize to form part of a heteroaryl or        heterocycloalkyl group unsubstituted or substituted with one two        or three suitable substituents selected from halogen, ═O; ═S;        —CN; —NO₂, or an alkyl, alkenyl, heteroalkyl, haloalkyl,        alkynyl, aryl, cycloalkyl, heterocycloalkyl, heteroaryl group        unsubstituted or substituted with one or more suitable        substituents independently selected from the group consisting        of: halogens; ═O; ═S; —CN; and —NO₂; and alkyl, alkenyl,        heteroalkyl, haloalkyl, alkynyl, aryl, cycloalkyl,        heterocycloalkyl, heteroaryl, —(CH₂)_(z)CN where z is a whole        integer, preferably from 0 to 4,    -   ═NH, —NHOH, —OH, —C(O)H, —OC(O)H, —C(O)OH, —OC(O)OH,        —OC(O)OC(O)H, —OOH, —C(NH)NH₂, —NHC(NH)NH₂, —C(S)NH₂,        —NHC(S)NH₂, —NHC(O)NH₂, —S(O₂)H, —S(O)H, —NH₂, —C(O)NH₂,        —OC(O)NH₂, —NHC(O)H, —NHC(O)OH, —C(O)NHC(O)H, —OS(O₂)H, —OS(O)H,        —OSH, —SC(O)H, —S(O)C(O)OH, —SO₂C(O)OH, —NHSH, —NHS(O)H,        —NHSO₂H, —C(O)SH, —C(O)S(O)H, —C(O)S(O₂)H, —C(S)H, —C(S)OH,        —C(SO)OH, —C(SO₂)OH, —NHC(S)H, —OC(S)H, —OC(S)OH, —OC(SO₂)H,        —S(O₂)NH₂, —S(O)NH₂, —SNH₂, —NHCS(O₂)H, —NHC(SO)H, —NHC(S)H, and        —SH groups unsubstituted or substituted with one or more        suitable substituents independently selected from the group        consisting of halogens, ═O, —NO₂, —CN, —(CH₂)_(z)—CN where z is        a whole integer, preferably from 0 to 4, —OR_(c), —NR_(c)OR_(c),        —NR_(c)R_(c), —C(O)NR_(c), —C(O)OR_(c), —C(O)R_(c),        —NR_(c)C(O)NR_(c)R_(c), —NR_(c)C(O)R_(c), —OC(O)OR_(c),        —OC(O)NR_(c)R_(c), —SR_(c), unsubstituted alkyl, unsubstituted        alkenyl, unsubstituted alkynyl, unsubstituted aryl,        unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and        unsubstituted heteroaryl, or two or more substituents cyclize to        form a fused or spiro polycyclic cycloalkyl, heterocycloalkyl,        aryl, or heteroaryl group, where each R_(c) is independently        selected from hydrogen, unsubstituted alkyl, unsubstituted        alkenyl, unsubstituted alkynyl, unsubstituted aryl,        unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, and        unsubstituted heteroaryl, or two or more R_(c) groups together        cyclize to form part of a heteroaryl or heterocycloalkyl group        unsubstituted or substituted with an unsubstituted alkyl group;    -   (b) Ar₁, Ar₂ and Ar₃ are each independently an aryl, heteroaryl,        cycloalkyl or heterocycloalkyl group unsubstituted or        substituted with one or more suitable substituents independently        selected from the group consisting of: halogens; ═O; ═S; —CN;        and —NO₂; and alkyl, alkenyl, heteroalkyl, haloalkyl, alkynyl,        aryl, cycloalkyl, heterocycloalkyl, heteroaryl, —(CH₂)_(z)CN        where z is a whole integer, preferably from 0 to 4, ═NH, —NHOH,        —OH, —C(O)H, —OC(O)H, —C(O)OH, —OC(O)OH, —OC(O)OC(O)H, —OOH,        —C(NH)NH₂, —NHC(NH)NH₂, —C(S)NH₂, —NHC(S)NH₂, —NHC(O)NH₂,        —S(O₂)H, —S(O)H, —NH₂, —C(O)NH₂, —OC(O)NH₂, —NHC(O)H, —NHC(O)OH,        —C(O)NHC(O)H, —OS(O₂)H, —OS(O)H, —OSH, —SC(O)H, —S(O)C(O)OH,        —SO₂C(O)OH, —NHSH, —NHS(O)H, —NHSO₂H, —C(O)SH, —C(O)S(O)H,        —C(O)S(O₂)H, —C(S)H, —C(S)OH, —C(SO)OH, —C(SO₂)OH, —NHC(S)H,        —OC(S)H, —OC(S)OH, —OC(SO₂)H, —S(O₂)NH₂, —S(O)NH₂, —SNH₂,        —NHCS(O₂)H, —NHC(SO)H, —NHC(S)H, and —SH groups unsubstituted or        substituted with one or more suitable substituents independently        selected from the group consisting of halogens, ═O, —NO₂, —CN,        —(CH₂)_(z)—CN where z is a whole integer, preferably from 0 to        4, —OR_(c), —NR_(c)OR_(c), —NR_(c)R_(c), —C(O)NR_(c),        —C(O)OR_(c), —C(O)R_(c), —NR_(c)C(O)NR_(c)R_(c),        —NR_(c)C(O)R_(c), —OC(O)OR_(c), —OC(O)NR_(c)R_(c), —SR_(c),        unsubstituted alkyl, unsubstituted alkenyl, unsubstituted        alkynyl, unsubstituted aryl, unsubstituted cycloalkyl,        unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or        two or more substituents cyclize to form a fused or spiro        polycyclic cycloalkyl, heterocycloalkyl, aryl, or heteroaryl        group, where each R_(c) is independently selected from hydrogen,        unsubstituted alkyl, unsubstituted alkenyl, unsubstituted        alkynyl, unsubstituted aryl, unsubstituted cycloalkyl,        unsubstituted heterocycloalkyl, and unsubstituted heteroaryl, or        two or more R_(c) groups together cyclize to form part of a        heteroaryl or heterocycloalkyl group unsubstituted or        substituted with an unsubstituted alkyl group;    -   (c) n, is 0, 1, 2, 3 or 4;    -   (d) n₂ is 0, 1, 2, 3 or 4;    -   (e) n₃ is 0, 1, 2, 3 or 4;    -   (f) Z_(a) is a bond or is selected from S, O, N, NR_(c),        C(O)NR_(c), NR_(c)C(O), and CR_(c), wherein R_(c) is a suitable        substituent selected from hydrogen, unsubstituted alkyl,        unsubstituted alkenyl, unsubstituted alkynyl, unsubstituted        aryl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl,        or unsubstituted heteroaryl group; and    -   (g) W_(a) is S or O;    -   or a pharmaceutically acceptable salt, pharmaceutically        acceptable N-oxide, isomer, derivative, pharmaceutically active        metabolite, pharmaceutically acceptable prodrug, or        pharmaceutically acceptable solvate thereof.

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

wherein:

-   -   M is substituted or unsubstituted heteroaryl, or substituted or        unsubstituted aryl;    -   N is a substituted or unsubstituted aryl, or substituted or        unsubstituted hetroaryl; and    -   K is    -   Y is O or S;    -   each R_(k) is independently H, halogen, substituted or        unsubstituted alkyl, —OH, substituted or unsubstituted alkoxy,        —OC(O)R₂, —NO₂, —N(R₂)₂, —SR₂, —C(O)R₂, —C(O)₂R₂, —C(O)N(R₂)₂,        or —N(R₂)C(O)R₂,    -   each R₂ is independently H, substituted or unsubstituted alkyl,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocyclyl, substituted or unsubstituted aryl,        or substituted or unsubstituted heteroaryl; or wherein two R₂        groups are linked together by an optionally substituted        alkylene; and    -   each n is independently 0, 1, 2, 3 or 4;        or an active metabolite, or a pharmaceutically acceptable        prodrug, isomer, pharmaceutically acceptable salt or solvate        thereof.

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

wherein:

-   -   each Z is independently C, CR₃, N, NR₃, O, or S, provided that        no more than two Z's are heteroatoms and wherein no two adjacent        Z's are O or S,        -   where R₃ is H, substituted or unsubstituted alkyl,            substituted or unsubstituted cycloalkyl, substituted or            unsubstituted heteroaryl, or substituted or unsubstituted            aryl; and    -   each R₁ is independently H, halogen, substituted or        unsubstituted alkyl, substituted or unsubstituted alkoxy,        substituted or unsubstituted cycloalkyl, substituted or        unsubstituted heterocyclyl, substituted or unsubstituted aryl,        substituted or unsubstituted heteroaryl, —OR_(c) —OH,        —OC(O)R_(c), —NO₂, —N(R_(c))₂, —SR_(c), S(O)_(j)R_(c) where j is        1 or 2, —NR_(c)C(O)R_(c), —C(O)N(R_(c))₂, C(O)₂R_(c), or        —C(O)R_(c); or two adjacent R₁'s, are taken together to form a        substituted or unsubstituted aryl or heteroaryl, where        -   each R_(c) is independently H, substituted or unsubstituted            alkyl, substituted or unsubstituted cycloalkyl, substituted            or unsubstituted aryl, or substituted or unsubstituted            heteroaryl.

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

wherein Z₁ is CR₃ or N; and Z₂ is O or S.

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

wherein:

-   -   each R₁ is independently H, halogen, substituted or        unsubstituted alkyl, —O(substituted or unsubstituted alkyl),        —O(substituted or unsubstituted alkenyl),        —NR_(c)(O)O(substituted or unsubstituted alkyl), —NR_(c)C(O)        (substituted or unsubstituted alkyl), —NR_(c)C(O)(substituted or        unsubstituted alkenyl), —C(O)NR_(c)(substituted or unsubstituted        alkyl), —C(O)NR_(c)(substituted or unsubstituted alkenyl), —NO₂,        —S(═O)R_(c), —SR_(c), C(O)₂R_(c), or —C(O)R_(c); and    -   each R₂ is independently H or substituted or unsubstituted        alkyl.

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

wherein Z₁ is O or S; and Z₂ is CR₃ or N.

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

wherein:

-   -   each R₁ is independently H, halogen, substituted or        unsubstituted. alkyl, —O(substituted or unsubstituted alkyl),        —O(substituted or unsubstituted alkenyl),        —NR_(c)C(O)O(substituted or unsubstituted alkyl), —NR_(c)C(O)        (substituted or unsubstituted alkyl), —NR_(c)C(O)(substituted or        unsubstituted alkenyl), —C(O)NR_(c)(substituted or unsubstituted        alkyl), —C(O)NR_(c)(substituted or unsubstituted alkenyl), —NO₂,        —S(═O)R_(c), —SR_(c), C(O)₂R_(c), or —C(O)R_(c); and    -   each R₂ is independently H or substituted or unsubstituted        alkyl.

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

wherein:

-   -   L is a linker selected from the group consisting of a covalent        bond, substituted or unsubstituted alkenylene, substituted or        unsubstituted alkylene, —C(O)NH—, —C(O)—, —NH—, —O—, —S—,        —O(substituted or unsubstituted alkylene)-, —N(substituted or        unsubstituted alkylene)-, C(O)NH(substituted or unsubstituted        alkylene), C(O)NH(substituted or unsubstituted alkenylene)        —NHC(O)(substituted or unsubstituted alkylene)-,        —NHC(O)(substituted or unsubstituted alkenylene)-,        —C(O)(substituted or unsubstituted alkenylene)-, and        —NHC(O)(substituted or unsubstituted alkylene)S(substituted or        unsubstituted alkylene)C(O)NH—; and    -   T is a mono-, bi, -or tricyclic, substituted or unsubstituted        cycloalkyl, heterocyclyl, aryl, or heteroaryl.        In some embodiments, T is        wherein A is a substituted or unsubstituted five or six-membered        heterocyclyl, aryl, or heteroaryl; and B is a substituted or        unsubstituted five or six-membered heterocyclene, arylene, or        heteroarylene, wherein A and B together form a fused two ring        moiety.

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

In some embodiments, L of said compound is a covalent bond—C(O)NH(substituted or unsubstituted alkylene), —NHC(O)—,—NHC(O)(substituted or unsubstituted alkylene)-, —NH—, or —O(substitutedor unsubstituted alkylene)-.

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

In some embodiments, B of said compound is a substituted orunsubstituted five-membered arylene or heteroarylene. In otherembodiments, B is substituted or unsubstituted thiophenylene. In stillother embodiments, B is substituted or unsubstituted imidazolylene. Inyet other embodiments, B is substituted or unsubstituted pyrrolylene. Instill other embodiments, B of said compound is a substituted orunsubstituted 6-membered arylene or heteroarylene. In some embodiments,B is substituted or unsubstituted phenylene. In other embodiments, B issubstituted or unsubstituted pyridinylene, pyrimidinylene, orpyridazine.

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

In some embodiments, B of said compound is a substituted orunsubstituted six-membered heteroarylene. In other embodiments, thesix-membered heteroarylene is substituted or unsubstitutedpyrimidinylene. In still other embodiments, L of said compound —OCH₂—.In yet other embodiments, L of said compound is —C(O)NH.

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

wherein:

-   -   L is a linker selected from the group consisting of a covalent        bond, substituted or unsubstituted alkenylene, substituted or        unsubstituted alkylene, —C(O)NH—, —C(O)—, —NH—, —O—, —S—,        —O(substituted or unsubstituted alkylene)-, —N(substituted or        unsubstituted alkylene)-, —C(O)NH(substituted or unsubstituted        alkylene)-, —C(O)NH(substituted or unsubstituted alkenylene)-        —NHC(O)(substituted or unsubstituted alkylene)-,        —NHC(O)(substituted or unsubstituted alkenylene)-,        —C(O)(substituted or unsubstituted alkenylene)-, and        —NHC(O)(substituted or unsubstituted alkylene)S(substituted or        unsubstituted alkylene)C(O)NH—; and    -   each of X₁-X₅ is independently C, CR, N, NR, S, or O, wherein no        more than three of X₁-X₅ is a heteroatom, and no two adjacent        ring atoms are O or S; where each R is independently H, halogen,        substituted or unsubstituted alkyl, —OR_(d), substituted or        unsubstituted alkoxy, —OC(O)R_(d), —NO₂, —N(R_(d))₂, —SR_(d),        —S(O)_(j)R_(d) where j is 1 or 2, —NR_(d)C(O)R_(d), —C(O)₂R_(d),        —C(O)N(R_(d))₂, or —C(O)R_(d), or two adjacent R's are taken        together to form a substituted or unsubstituted aryl or        hetroaryl, where        -   each R_(d) is independently H, substituted or unsubstituted            alkyl, substituted or unsubstituted cycloalkyl, substituted            or unsubstituted aryl or substituted or unsubstituted            heteroaryl.

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

In some embodiments, L of said compound is a covalent bond, —C(O)NH—, or—O(substituted or unsubstituted alkylene)-. In other embodiments,

of said compound is selected from the group consisting of:

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

wherein:

-   -   L is a linker selected from the group consisting of a covalent        bond, substituted or unsubstituted alkenylene, substituted or        unsubstituted alkylene, —C(O)NH—, —C(O)—, —NH—, —O—, —S—,        —O(substituted or unsubstituted alkylene)-, —N(substituted or        unsubstituted alkylene)-, —C(O)NH(substituted or unsubstituted        alkylene)-, —C(O)NH(substituted or unsubstituted alkenylene)-        —NHC(O)(substituted or unsubstituted alkylene)-,        —NHC(O)(substituted or unsubstituted alkenylene)-,        —C(O)(substituted or unsubstituted alkenylene)-, and        —NHC(O)(substituted or unsubstituted alkylene)S(substituted or        unsubstituted alkylene)C(O)NH—; and    -   each of X₁-X₅ is independently C, CR, N—O, or N, wherein no more        than two of X₁-X₅ is N, where    -   each R is independently H, halogen, substituted or unsubstituted        alkyl, —OR_(d), substituted or unsubstituted alkoxy,        —OC(O)R_(d), —NO₂, —N(R_(d))₂, —SR_(d), —S(O)_(j)R_(d) where j        is 1 or 2, —NR_(d)C(O)R_(d), —C(O)₂R_(d), —C(O)N(R_(d))₂, or        —C(O)R_(d), or two adjacent R's are taken together to form a        substituted or unsubstituted aryl or hetroaryl, where        -   each R_(d) is independently H, substituted or unsubstituted            alkyl, substituted or unsubstituted cycloalkyl, substituted            or unsubstituted aryl or substituted or unsubstituted            heteroaryl.

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a-flt-3 modulating compound having the structure:

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

wherein L is —O(substituted or unsubstituted alkylene)- or—(O)(substituted or unsubstituted alkenylene)-.

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

In some embodiments, L of said compound is —O(substituted orunsubstituted alkylene)- or —O(substituted or unsubstitutedalkenylene)-. In other embodiments, L of said compound is —NHC(O)—. Instill other embodiments, L of said compound is a covalent bond,substituted or unsubstituted alkylene, —NHC(O)(substituted orunsubstituted alkylene)-, —NHC(O)(substituted or unsubstitutedalkenylene)-, —NH(alkylene)-, —NHC(O)CH₂SCH₂C(O)NH—, and—NHC(O)(substituted alkylene)S—.

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

wherein:

-   -   L is a linker selected from the group consisting of a covalent        bond, substituted or unsubstituted alkenylene, substituted or        unsubstituted alkylene, —C(O)NH—, —C(O)—, —NH—, —O—, —S—,        —O(substituted or unsubstituted alkylene)-, —N(substituted or        unsubstituted alkylene)-, —C(O)NH(substituted or unsubstituted        alkylene)-, —C(O)NH(substituted or unsubstituted alkenylene)-        —NHC(O)(substituted or unsubstituted alkylene)-,        —NHC(O)(substituted or unsubstituted alkenylene)-,        —C(O)(substituted or unsubstituted alkenylene)-, and        —NHC(O)(substituted or unsubstituted alkylene)S(substituted or        unsubstituted alkylene)C(O)NH—; and    -   each of X₁-X₅ is independently C, CR, or N, wherein no more than        two of X₁-X₅ is N, where    -   each R is independently H, halogen, substituted or unsubstituted        alkyl, —OH, substituted or unsubstituted alkoxy, —OC(O)R_(d),        —NO₂, —N(R_(d))₂, —SR_(d), —S(O)_(j)R_(d) where j is 1 or 2,        —NR_(d)C(O)R_(d), —C(O)₂R_(d), —C(O)N(R_(d))₂ or —C(O)R_(d), or        two adjacent R's are taken together to form a substituted or        unsubstituted aryl or hetroaryl, where        -   each R_(d) is independently H, substituted or unsubstituted            alkyl, substituted or unsubstituted cycloalkyl, substituted            or unsubstituted aryl or substituted or unsubstituted            heteroaryl.    -   Z₁ is O or S; and    -   Z₂ is CR₃ or N.

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

wherein:

-   -   each of L and L₁ is independently a linker selected from the        group consisting of a covalent bond, substituted or        unsubstituted alkenylene, substituted or unsubstituted alkylene,        —C(O)NH—, —C(O)—, —NH—, —O—, —S—, —O(substituted or        unsubstituted alkylene)-, —N(substituted or unsubstituted        alkylene)-, —C(O)NH(substituted-or unsubstituted alkylene),        —C(O)NH(substituted or unsubstituted alkenylene)-        —NHC(O)(substituted or unsubstituted alkylene)-,        —NHC(O)(substituted or unsubstituted alkenylene)-,        —C(O)(substituted or unsubstituted alkenylene)-, and        —NHC(O)(substituted or unsubstituted alkylene)S(substituted or        unsubstituted alkylene)C(O)NH—;    -   U is a substituted or unsubstituted cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl; and    -   V is a substituted or unsubstituted cycloalkylene,        heterocyclene, arylene, or heteroarylene.

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

wherein:

-   -   each of X₁-X₅ is independently C, CR, N, NR, S, or O, wherein no        more than three of X₁-X₅ is a heteroatom, and no two adjacent        ring atoms are O or S; and        -   each R is independently H, halogen, substituted or            unsubstituted alkyl, —OR_(d), substituted or unsubstituted            alkoxy, —OC(O)R_(d), —NO₂, —N(R_(d))₂, —SR_(d),            —S(O)_(j)R_(d) where j is 1 or 2, —NR_(d)C(O)R_(d),            —C(O)₂R_(d), —C(O)N(R_(d))₂ or —C(O)R_(d), or two adjacent            R's are taken together to form a substituted or            unsubstituted aryl or hetroaryl, where        -   each R_(d) is independently H, substituted or unsubstituted            alkyl, substituted or unsubstituted cycloalkyl, substituted            or unsubstituted aryl or substituted or unsubstituted            heteroaryl.            In some embodiments, U is a substituted or unsubstituted            five-membered heteroaryl, substituted or unsubstituted            phenyl, or substituted or unsubstituted six-membered            heteroaryl.

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

wherein:

-   -   Z₃ is NR₃, O, or S; and    -   Z₄ is N or CR₃.

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

wherein:

-   -   L is a linker selected from the group consisting of a covalent        bond, substituted or unsubstituted alkenylene, substituted or        unsubstituted alkylene, —C(O)NH—, —C(O)—, —NH—, —O—, —S—,        —O(substituted or unsubstituted alkylene)-, —N(substituted or        unsubstituted alkylene)-, —C(O)NH(substituted or unsubstituted        alkylene)-, —C(O)NH(substituted or unsubstituted alkenylene)-        —NHC(O)(substituted or unsubstituted alkylene)-,        —NHC(O)(substituted or unsubstituted alkenylene)-,        —C(O)(substituted or unsubstituted alkenylene)-, and        —NHC(O)(substituted or unsubstituted alkylene)S(substituted or        unsubstituted alkylene)C(O)NH—; and    -   T is a substituted or unsubstituted cycloalkyl,        heterocycloalkyl, aryl, or heteroaryl.

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

wherein:

-   -   each Z is independently C, CR₃, N, NR₃, O, or S, provided that        no more than two Z's are heteroatoms where        -   R₃ is H, substituted or unsubstituted alkyl, substituted or            unsubstituted cycloalkyl, substituted or unsubstituted            heteroaryl, or substituted or unsubstituted aryl.            -   each R_(k) is independently H, halogen, substituted or                unsubstituted alkyl, —OH, substituted or unsubstituted                alkoxy, —OC(O)R₂, —NO₂, —N(R₂)₂, —SR₂, —C(O)R₂,                —C(O)₂R₂, —C(O)N(R₂)₂, or —N(R₂)C(O)R₂,        -   each R₂ is independently H, substituted or unsubstituted            alkyl, substituted or unsubstituted cycloalkyl, substituted            or unsubstituted heterocyclyl, substituted or unsubstituted            aryl, or substituted or unsubstituted heteroaryl; or wherein            two R₂ groups are linked together by an optionally            substituted alkylene; and        -   each R₁ is independently H, halogen, substituted or            unsubstituted alkyl, substituted or unsubstituted alkoxy,            substituted or unsubstituted cycloalkyl, substituted or            unsubstituted heterocyclyl, substituted or unsubstituted            aryl, substituted or unsubstituted heteroaryl, —OR_(c) —OH,            —OC(O)R_(c), —NO₂, —N(R_(c))₂, —SR_(c), S(O)_(j)R_(c) where            j is 1 or 2, —NR_(c)C(O)R_(c), —C(O)N(R_(c))₂, —C(O)₂R_(c),            or —C(O)R_(c); or two adjacent R₁'s, are taken together to            form a substituted or unsubstituted aryl or heteroaryl,            where            -   each R_(c) is independently H, substituted or                unsubstituted alkyl, substituted or unsubstituted                cycloalkyl, substituted or unsubstituted aryl, or                substituted or unsubstituted heteroaryl.

Provided herein are compositions and methods for treating a diseasecomprising administering to a subject in need thereof an effectiveamount of a flt-3 modulating compound having the structure:

In some embodiments, the protein tyrosine kinase is selected from thefetus liver kinase (“flk”) receptor subfamily, which includes kinaseinsert domain-receptor fetal liver kinase-1 (KDR/FLK-1), flk-1R, flk-4and fms-like tyrosine kinase 1 (flt-1). In further embodiments, theprotein tyrosine kinase is selected from the fibroblast growth factor(“FGF”) receptor subgroup, which includes the receptors FGFR1, FGFR 2,FGFR3, and FGFR4, and the ligands, FGF1, FGF2, FGF3, FGF4, FGF5,FGF6,and FGF7. In a still further embodiment, the protein tyrosinekinase is the tyrosine kinase growth factor receptor family, c-Met. Insome embodiments, the protein tyrosine kinase is an fins-like tyrosinekinase 3 receptor kinase (FLT-3 kinase).

The compounds and compositions disclosed herein may be used for theprevention or treatment of cancers such as stomach, gastric, bone,ovary, colon, lung, brain, larynx, lymphatic system, genitourinarytract, ovarian, squamous cell carcinoma, astrocytoma, Kaposi's sarcoma,glioblastoma, lung cancer, bladder cancer, head and neck cancer,melanoma, ovarian cancer, prostate cancer, breast cancer, small-celllung cancer, leukemia, glioma, colorectal cancer, genitourinary cancergastrointestinal cancer, or pancreatic cancer. In particular, the canceris acute myelogenous leukemia (AML), B-precursor cell acutelymphoblastic leukemias, myelodysplastic leukemias, T-cell acutelymphoblastic leukemias, and chronic myelogenous leukemias (CMLs).

Compositions and methods for treating a disease comprising administeringto a subject in need thereof an effective amount of an fms-like tyrosinekinase 3 (FLT-3) receptor modulating compound are provided herein. Inone embodiment, the disease is cancer. In other embodiments, the canceris a malignant tumor, or a hematologic malignancy such as leukemia andlymphoma. In some embodiments, the leukemia is acute myelogenousleukemia (AML), a B-precursor cell acute lymphoblastic leukemia,myelodysplastic leukemia, T-cell acute lymphoblastic leukemia or chronicmyelogenous leukemia (CML).

These and other aspects of the present invention will become evidentupon reference to the following detailed description. In addition,various references are set forth herein which describe in more detailcertain procedures or compositions, and are incorporated by reference intheir entirety.

DISCLOSURE OF THE INVENTION

To more readily facilitate an understanding of the invention and itspreferred embodiments, the meanings of terms used herein will becomeapparent from the context of this specification in view of common usageof various terms and the explicit definitions of other terms provided inthe glossary below or in the ensuing description.

Glossary of Terms

Unless otherwise stated, the following terms used in this application,including the specification and claims, have the definitions givenbelow. It must be noted that, as used in the specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Definition ofstandard chemistry terms may be found in reference works, includingCarey and Sundberg (1992) “ADVANCED ORGANIC CHEMISTRY 3^(RD) ED.” Vols.A and B, Plenum Press, New York. Unless otherwise indicated,conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry,biochemistry, recombinant DNA techniques and pharmacology, within theskill of the art are employed.

The term “modulator” means a molecule that interacts with a targeteither directly or indirectly. The interactions include, but are notlimited to, agonist, antagonist, and the like.

The term “agonist” means a molecule such as a compound, a drug, anenzyme activator or a hormone that enhances the activity of anothermolecule or the activity of a receptor site etiehr directly orindirectly.

The term “antagonist” means a molecule such as a compound, a drug, anenzyme inhibitor, or a hormone, that diminishes or prevents the actionof another molecule or the activity of a receptor site either directlyor indirectly.

The terms “effective amount” or “therapeutically effective amount” referto a sufficient amount of the agent to provide the desired biologicalresult. That result can be reduction and/or alleviation of the signs,symptoms, or causes of a disease, or any other desired alteration of abiological system. For example, an “effective amount” for therapeuticuse is the amount of the composition comprising a compound as disclosedherein required to provide a clinically significant decrease in adisease. An appropriate “effective” amount in any individual case may bedetermined by one of ordinary skill in the art using routineexperimentation.

As used herein, the terms “treat” or “treatment” are synonymous with theterm “prevent” and are meant to indicate a postponement of developmentof diseases, preventing the development of diseases, and/or reducingseverity of such symptoms that will or are expected to develop. Thus,these terms include ameliorating existing disease symptoms, preventingadditional symptoms, ameliorating or preventing the underlying metaboliccauses of symptoms, inhibiting the disorder or disease, e.g., arrestingthe development of the disorder or disease, relieving the disorder ordisease, causing regression of the disorder or disease, relieving acondition caused by the disease or disorder, or stopping the symptoms ofthe disease or disorder.

By “pharmaceutically acceptable” or “pharmacologically acceptable” ismeant a material which is not biologically or otherwise undesirable,i.e., the material may be administered to an individual without causingany undesirable biological effects or interacting in a deleteriousmanner with any of the components of the composition in which it iscontained.

“Carrier materials” include any commonly used excipients inpharmaceutics and should be selected on the basis of compatibility andthe release profile properties of the desired dosage form. Exemplarycarrier materials include, e.g., binders, suspending agents,disintegration agents, filling agents, surfactants, solubilizers,stabilizers, lubricants, wetting agents, diluents, and the like.“Pharmaceutically compatible carrier materials” may comprise, e.g.,acacia, gelatin, colloidal silicon dioxide, calcium glycerophosphate,calcium lactate, maltodextrin, glycerine, magnesium silicate, sodiumcaseinate, soy lecithin, sodium chloride, tricalcium phosphate,dipotassium phosphate, sodium stearoyl lactylate, carrageenan,monoglyceride, diglyceride, pregelatinized starch, and the like. See,e.g., Remington: The Science and Practice of Pharmacy, Nineteenth Ed(Easton, Pa.: Mack Publishing Company, 1995); Hoover, John E.,Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pa.1975; Liberman, H. A. and Lachman, L., Eds., Pharmaceutical DosageForms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical DosageForms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams &Wilkins1999).

As used herein, the term “subject” encompasses mammals and non-mammals.Examples of mammals include, but are not limited to, any member of theMammalian class: humans, non-human primates such as chimpanzees, andother apes and monkey species; farm animals such as cattle, horses,sheep, goats, swine; domestic animals such as rabbits, dogs, and cats;laboratory animals including rodents, such as rats, mice and guineapigs, and the like. Examples of non-mammals include, but are not limitedto, birds, fish and the like. In one embodiment of the presentinvention, the mammal is a human.

The term “pharmaceutically acceptable salt” of a compound means a saltthat is pharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts, forexample, include: (1) acid addition salts, formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,2-naphthalenesulfonic acid,4-methylbicyclo-[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid,4,4,-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionicacid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuricacid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylicacid, stearic acid, muconic acid, and the like; (2) salts formed when anacidic proton present in the parent compound either is replaced by ametal ion, e.g., an alkali metal ion, an alkaline earth ion, or analuminum ion; or coordinates with an organic base. Acceptable organicbases include ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like. Acceptable inorganicbases include aluminum hydroxide, calcium hydroxide, potassiumhydroxide, sodium carbonate, sodium hydroxide, and the like. It shouldbe understood that a reference to a pharmaceutically acceptable saltincludes the solvent addition forms or crystal forms thereof,particularly solvates or polymorphs. Solvates contain eitherstoichiometric or non-stoichiometric amounts of a solvent, and are oftenformed during the process of crystallization. Hydrates are formed whenthe solvent is water, or alcoholates are formed when the solvent isalcohol. Polymorphs include the different crystal packing arrangementsof the same elemental composition of a compound. Polymorphs usually havedifferent X-ray diffraction patterns, infrared spectra, melting points,density, hardness, crystal shape, optical and electrical properties,stability, and solubility. Various factors such as the recrystallizationsolvent, rate of crystallization, and storage temperature may cause asingle crystal form to dominate.

As used herein, the term “biological sample” is broadly defined toinclude any cell, tissue, organ or multicellular organism. A biologicalsample can be derived, for example, from cell or tissue cultures invitro. Alternatively, a biological sample can be derived from a livingorganism or from a population of single cell organisms.

As used herein, the term “linker” means any divalent linking moiety usedto connect, join, or attach two chemical groups. For example, linkersmay be used to join two cyclic groups, such as to join two aryl groups(e.g., phenyl), an aryl group to a cycloalkyl group, an aryl group to aheterocyclyl group, a cycloalkyl group to a cycloalkyl group, acycloalkyl group to a heterocyclyl group, and the like. Representativelinkers include, but are not limited to, a covalent bond, -(substitutedor unsubstituted alkylene)-, -(substituted or unsubstitutedalkenylene)-, -(substituted or unsubstituted alkynylene)-, -(substitutedor unsubstituted cycloalkylene)-, -(substituted or unsubstitutedheterocyclylene)-, -(substituted or unsubstituted arylene)-, and-(substituted or unsubstituted heteroarylene)-. Exemplary linkers alsoinclude —O—, —S—, —S(O)—, —S(O)₂—, —S(O)₃—, —C(O)—, —NH—, —N═, —N═N—,═N—N═, —C(O)NH—, —S(O)NH—, and the like. Additional examples of linkersinclude —O(substituted or unsubstituted alkylene)-, —N(substituted orunsubstituted alkylene)-, —NHC(O)(substituted or unsubstitutedalkylene)-, —C(O)(substituted or unsubstituted alkenylene)-—NHC(O)(substituted or unsubstituted alkylene)S(substituted orunsubstituted alkylene)C(O)NH—, —NHC(O)(substituted or unsubstitutedalkenylene)-, and the like. Linkers, as represented herein, embracedivalent moieties in any chemically feasible directionality. Forexample, compounds comprising a linker —C(O)NH— which attaches two arylgroups, Ar₁ to Ar₂, include Ar₁—C(O)NH—Ar₂ as well as Ar₁—NHC(O)—Ar₂.

As used herein, the term “halogen” includes fluorine, chlorine, bromine,and iodine.

As used herein, “alkyl” means a straight chain or branched, saturated orunsaturated chain having from 1 to 10 carbon atoms. Representativesaturated alkyl groups include, but are not limited to, methyl, ethyl,n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl,2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl,2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl,4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl,4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2-ethyl-1-butyl, butyl, isobutyl, t-butyl, n-pentyl, isopentyl,neopentyl, and n-hexyl, and longer alkyl groups, such as heptyl, andoctyl. An alkyl group can be unsubstituted or substituted. Unsaturatedalkyl groups include alkenyl groups and alkynyl groups, discussed below.Alkyl groups containing three or more carbon atoms may be straight,branched or cyclized.

As used herein, “lower alkyl” means an alkyl having from 1 to 5 carbonatoms.

As used herein, an “alkenyl group” includes a monovalent unbranched orbranched hydrocarbon chain having one or more double bonds therein. Thedouble bond of an alkenyl group can be unconjugated or conjugated toanother unsaturated group. Suitable alkenyl groups include, but are notlimited to, (C₂-C₈) alkenyl groups, such as vinyl, allyl, butenyl,pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2-ethylhexenyl,2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl. An alkenyl group canbe unsubstituted or substituted.

As used herein, “alkynyl group” includes a monovalent unbranched orbranched hydrocarbon chain having one or more triple bonds therein. Thetriple bond of an alkynyl group can be unconjugated or conjugated toanother unsaturated group. Suitable alkynyl groups include, but are notlimited to, (C₂-C₆)alkynyl groups, such as ethynyl, propynyl, butynyl,pentynyl, hexynyl, methylpropynyl, 4-methyl-1-butynyl,4-propyl-2-pentynyl, and 4-butyl-2-hexynyl. An alkynyl group can beunsubstituted or substituted.

The terms “trifluoromethyl,” “sulfonyl,” and “carboxyl” include CF₃,SO₃H, and CO₂H, respectively.

The term “alkoxy” as used herein includes —O-(alkyl), wherein alkyl isdefined above.

As used herein, “alkoxyalkoxy” includes —O-(alkyl)-O-(alkyl), whereineach “alkyl” is independently an alkyl group defined above.

As used herein, “alkoxycarbonyl” includes-C(O)O-(alkyl), wherein alkylis defined above.

As used herein, “alkoxycarbonylalkyl” includes -(alkyl)-C(O)O-(alkyl),wherein alkyl is defined above.

As used herein, “alkoxyalkyl” means -(alkyl)-O-(alkyl), wherein each“alkyl” is independently an alkyl group defined above.

As used herein, the term “aryl” (Ar) refers to a monocyclic, or fused orspiro polycyclic, aromatic carbocycle (ring structure having ring atomsthat are all carbon) having from 3 to 12 ring atoms per ring.Illustrative examples of aryl groups include the following moieties:

As used herein, the term “heteroaryl” (heteroAr) refers to a monocyclic,or fused or spiro polycyclic, aromatic heterocycle (ring structurehaving ring atoms selected from carbon atoms as well as nitrogen,oxygen, and sulfur heteroatoms) having from 3 to 12 ring atoms per ring.Illustrative examples of aryl groups include the following moieties:

As used herein, the term “cycloalkyl” refers to a saturated or partiallysaturated, monocyclic or fused or Spiro polycyclic, carbocycle havingfrom 3 to 12 ring atoms per ring. Illustrative examples of cycloalkylgroups include the following moieties:

As used herein, the term “heterocycloalkyl” refers to a monocyclic, orfused or spiro polycyclic, ring structure that is saturated or partiallysaturated and has from 3 to 12 ring atoms per ring selected from C atomsand N, O, and S heteroatoms. Illustrative examples of heterocycloalkylgroups include:

As used herein, “aryloxy” includes —O-aryl group, wherein aryl is asdefined above. An aryloxy group can be unsubstituted or substituted.

As used herein, “arylalkyl” includes -(alkyl)-(aryl), wherein alkyl andaryl are defined above.

As used herein, “arylalkyloxy” includes —O-(alkyl)-(aryl), wherein alkyland aryl are defined above.

As used herein, “cycloalkyl” includes a monocyclic or polycyclicsaturated ring comprising carbon and hydrogen atoms and having nocarbon-carbon multiple bonds. Examples of cycloalkyl groups include, butare not limited to, (C₃-C₇)cycloalkyl groups, such as cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl, and saturatedcyclic and bicyclic terpenes. A cycloalkyl group can be unsubstituted orsubstituted. Preferably, the cycloalkyl group is a monocyclic ring orbicyclic ring.

As used herein, “cycloalkyloxy” includes —O-(cycloalkyl), whereincycloalkyl is defined above.

As used herein, “cycloalkylalkyloxy” includes —O-(alkyl)-(cycloalkyl),wherein cycloalkyl and alkyl are defined above.

As used herein, the term “alkylidene” includes the divalent radical—C_(n)H_(2n)—, wherein n is an integer from 1 to 8, such as —CH₂—,—CH₂CH₂—, —CH₂—CH₂—CH₂—, —CH₂CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂CH₂—, and thelike, unsubstituted or substituted with one or more alkyl groups.

As used herein, “heteroatom-containing alkylidene” includes analkylidene wherein at least one carbon atom is replaced by a heteroatomselected from nitrogen, oxygen, or sulfur, such as —CH₂CH₂OCH₂CH₂—, andthe like, unsubstituted or substituted with one or more alkyl groups.

As used herein, “aminoalkoxy” includes —O-(alkyl)-NH₂, wherein alkyl isdefined above.

As used herein, “mono-alkylamino” includes —NH(alkyl), wherein alkyl isdefined above.

As used herein, “di-alkylamino” includes —N(alkyl)(alkyl), wherein each“alkyl” is independently an alkyl group defined above.

As used herein, “mono-alkylaminoalkoxy” includes —O-(alkyl)-NH(alkyl),wherein each “alkyl” is independently an alkyl group defined above.

As used herein, “di-alkylaminoalkoxy” includes—O-(alkyl)N(alkyl)(alkyl), wherein each “alkyl” is independently analkyl group defined above.

As used herein, “arylamino” includes —NH(aryl), wherein aryl is definedabove.

As used herein, “arylalkylamino” includes —NH-(alkyl)-(aryl), whereinalkyl and aryl are defined above.

As used herein, “alkylamino” includes —NH(alkyl), wherein alkyl isdefined above.

As used herein, “cycloalkylamino” includes —NH-(cycloalkyl), whereincyclohexyl is defined above.

As used herein, “cycloalkylalkylamino” includes—NH-(alkyl)-(cycloalkyl), wherein alkyl and cycloalkyl are definedabove.

As used herein, “aminoalkyl” includes -(alkyl)-NH₂, wherein alkyl isdefined above.

As used herein, “mono-alkylaminoalkyl” includes-(alkyl)-NH(alkyl),wherein each “alkyl” is independently an alkyl groupdefined above.

As used herein, “di-alkylaminoalkyl” includes-(alkyl)-N(alkyl)(alkyl),wherein each “alkyl” is independently an alkylgroup defined above.

The term “whole integer” is intended to include whole numbers. Forexample, a whole integer from 0 to 4 would include 0, 1, 2, 3, and 4.

Sulfonyl refers to the presence of a sulfur atom, which is optionallylinked to another moiety such as an aliphatic group, an aromatic group,an aryl group, an alicyclic group, or a heterocyclic group. Aryl oralkyl sulfonyl moieties have the formula —SO₂R_(d), and alkoxy moietieshave the formula —O—R_(d)—, wherein R_(d) is alkyl, as defined above, oris aryl wherein aryl is phenyl, optionally substituted with 1-3substituents independently selected from halo (fluoro, chloro, bromo oriodo), lower alkyl (1-6C) and lower alkoxy (1-6C).

As used herein, the term “substituted” means that the specified group ormoiety bears one or more suitable substituents.

As used herein, the term “unsubstituted” means that the specified groupbears no substituents.

As used herein, the term “optionally substituted” means that thespecified group is unsubstituted or substituted by one or moresubstituents.

Molecular embodiments of the present invention may possess one or morechiral centers and each center may exist in the R or S configuration.The present invention includes all diastereomeric, enantiomeric, andepimeric forms as well as the appropriate mixtures thereof.Stereoisomers may be obtained, if desired, by methods known in the artas, for example, the separation of stereoisomers by chiralchromatographic columns. Additionally, the compounds of the presentinvention may exist as geometric isomers. The present invention includesall cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers aswell as the appropriate mixtures thereof.

Certain functional groups contained within the compounds of the presentinvention can be substituted for bioisosteric groups, that is, groupswhich have similar spatial or electronic requirements to the parentgroup, but exhibit differing or improved physicochemical or otherproperties. Suitable examples are well known to those of skill in theart, and include, but are not limited to moieties described in Patini etal., Chem, Rev, 1996, 96, 3147-3176 and references cited therein.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

To more readily facilitate an understanding of the invention and itspreferred embodiments, the meanings of terms used herein will becomeapparent from the context of this specification in view of common usageof various terms and the explicit definitions of other terms provided inthe glossary below or in the ensuing description.

Compounds

In one aspect, the present invention is directed to compounds,compositions, and methods for treating conditions associated withabnormal kinase activity. In one embodiment, compounds useful in theinvention are derivatives of isoxazoles, pyrazoles and isothiazoles.When the compounds of the invention contain one or more chiral centers,the invention includes optically pure forms as well as mixtures ofstereoisomers or enantiomers.

Thus, the invention provides methods for modulating various kinases byproviding an effective amount of a compound of the formulas describedherein.

Salts of the compounds may be used for therapeutic and prophylacticpurposes, where the salt is preferably a pharmaceutically acceptablesalt. Examples of pharmaceutically acceptable salts include thosederived from mineral acids, such as hydrochloric, hydrobromic,phosphoric, metaphosphoric, nitric and sulphuric acids, and organicacids, such as tartaric, acetic, trifluoroacetic, citric, malic, lactic,fumaric, benzoic, glycolic, gluconic, succinic and methanesulphonic andarylsulphonic, for example Q-toluenesulphonic, acids.

A “prodrug” refers to a drug or compound in which the pharmacologicalaction results from conversion by metabolic processes within the body.Prodrugs are generally drug precursors that, following administration toa subject and subsequent absorption, are converted to an active, or amore active species via some process, such as conversion by a metabolicpathway. Some prodrugs have a chemical group present on the prodrug thatrenders it less active and/or confers solubility or some other propertyto the drug. Once the chemical group has been cleaved and/or modifiedfrom the prodrug the active drug is generated. Prodrugs may be designedas reversible drug derivatives, for use as modifiers to enhance drugtransport to site-specific tissues. Additionally, prodrugs can increasethe effective water solubility of the therapeutic compound for targetingto regions where water is the principal solvent. See, e.g., Fedorak etal., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastroenterol,106:405-413 (1994); Hochhaus et al., Biomed. Chrom., 6:283-286 (1992);J. Larsen and H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J.Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J.Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs asNovel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; andEdward B. Roche, Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press, 1987. Prodrug forms ofthe above described compounds, wherein the prodrug is metabolized invivo to produce a derivative as set forth above are included within thescope of the claims. Indeed, some of the above-described derivatives maybe a prodrug for another derivative or active compound.

The invention further provides for the optical isomers of the compoundsdisclosed herein, especially those resulting from the chiral carbonatoms in the molecule. In additional embodiments of the invention,mixtures of enantiomers and/or diastereoisomers, resulting from a singlepreparative step, combination, or interconversion may also be useful forthe applications described herein.

In another aspect, compositions containing the above described analogsand derivatives are provided. Preferably, the compositions areformulated to be suitable for pharmaceutical or clinical use by theinclusion of appropriate carriers or excipients.

Groups such as carbonyl, carboxyl, alkoxy, amino, and cyano groups,etc., as shown in the formula above, need not be directly bound to thepara position; they may be included elsewhere in the alkyl, alkenyl oralkynyl substituent. Thus, also acceptable substituents are thefollowing representative forms:

-   -   —CH₂NHCH₃; —CH₂OCH₃; —CH₂SCH₃; —NHCH₃; —CH₂CH₃; —OCH₂CH₃;        —SCH₂CH₂CH₃; —CH═CHCH₂NH₂; —CH₂CH₂OH;        —CH₂CH₂CH₂SH; —CH₂OC(O)CH₃; —CH₂NHC(O)CH₂C(O)CH₃;        —NHC(O)CH₂CH₂CH₃ each of which may further be substituted with a        cycloalkyl, heterocycloalkyl, aryl or heteroaryl group.

It will also be evident that these substituents include, for example,trifluoromethyl, difluoromethyl and fluoromethyl (alkyl substituted byhalo) and trifluoromethoxy, difluoromethoxy and fluoromethoxy (alkylwhere one carbon is replaced by O and is further substituted by halo).

Compounds of the invention which contain carboxyl groups or whichcontain amino groups may be supplied in the forms of theirpharmaceutically acceptable salts. Pharmaceutically acceptable salts ofcarboxylic acids include inorganic salts such as salts of sodium,potassium, calcium, magnesium and the like or salts formed with organicbases such as caffeine. Salts of amines are acid addition salts formedfrom inorganic acids such as hydrochloric, sulfuric, phosphoric acids ormay be salts of organic acids such as acetates, maleates, propionates,and the like.

The invention also provides prodrug forms of the compounds describedherein, wherein the prodrug is metabolized in vivo to produce aderivative as set forth above. Indeed, some of the above describedderivatives may be a prodrug for another derivative or active compound.The invention further provides for the optical isomers of the compoundsdisclosed herein, especially those resulting from the chiral carbonatoms in the molecule. In additional embodiments of the invention,mixtures of enantiomers and/or diastereoisomers, resulting from a singlepreparative step, combination, or interconversion are provided.

In another aspect of the invention, compositions containing the abovedescribed analogs and derivatives are provided. Preferably, thecompositions are formulated to be suitable for pharmaceutical orclinical use by the inclusion of appropriate carriers or excipients.

In yet another aspect of the invention, pharmaceutical formulations areprovided comprising at least one compound described above, or apharmaceutically acceptable salt or solvate thereof, together with oneor more pharmaceutically acceptable carriers, diluents or excipients.

The compounds of the invention, especially when used in the inventionmethods and compositions, may be “conjugated”—that is they may becoupled to additional moieties that do not destroy their ability tomodulate kinases. For example, the compounds might be coupled to a labelsuch as a radioactive label, a fluorescent label and the like, or may becoupled to targeting agents such as antibodies or fragments, or tofragments to aid purification such as FLAG or a histidine tag. Thecompounds may also be coupled to specific binding partners such asbiotin for use in assay procedures or to moieties that alter theirbiological half-lives such as polyethylene glycol. Thus, the methods ofthe invention employ the invention compounds per se as well asconjugates thereof.

Synthesis of Compounds

Compounds of the present invention may be synthesized using standardsynthetic techniques known to those of skill in the art or using methodsknown in the art in combination with methods described herein. See,e.g., March, ADVANCED ORGANIC CHEMISTRY 4^(th) Ed., (Wiley 1992); Careyand Sundberg, ADVANCED ORGANIC CHEMISTRY 3^(rd) Ed., Vols. A and B(Plenum 1992), and Green and Wuts, PROTECTIVE GROUPS IN ORGANICSYNTHESIS 2^(nd) Ed. (Wiley 1991). General methods for the preparationof compound as disclosed herein may be derived from known reactions inthe field, and the reactions may be modified by the use of appropriatereagents and conditions, as would be recognized by the skilled person,for the introduction of the various moieties found in the formulae asprovided herein.

The compounds of the invention are synthesized by methods well known inthe art. The compounds of the invention are ureas or cyclic formsthereof and can be synthesized using generally known procedures for ureasynthesis.

In one group of methods, an amine is reacted with an isocyanate in anaprotic solvent. Typically, in some embodiments, a molar excess of theamine is used in the presence of an aprotic solvent and the reaction isconducted at room temperature. The reaction mixture is then poured intowater and precipitated with salt to recover the crude product which isthen purified according to standard methods.

In alternative methods, the ureas are formed from two separate aminereactants in the presence of a condensing agent such as1,1,carbonyldiimidazole (CDI) in the presence of an inert nonpolarsolvent such as dichloromethane. One of the amines is first added to asolution of CDI in solvent under cooling conditions and then stirred atroom temperature with the other amine. After removal of solvent, thecrude product can be purified using standard procedures.

In still another method, one of the amines is added in an aproticsolvent to a solution of triphosgene and then treated with the otheramine reactant dissolved in an inert solvent in the presence of basesuch as triethylamine. After reaction at room temperature, the mixturemay be diluted with, for example, ethylacetate and washed with water andbrine, dried and purified.

In still another method, one of the amine components is treated with4-nitrophenylchloroformate in the presence of mild base in a solventsuch as N-methylpyrrolidone (NMP). The other amine is then added and thereaction mixture heated, then cooled, poured into water, extracted intochloroform and further purified.

Alternatively, the urea may be formed by the reaction of an amine withthe counterpart halo acylamine which is formed from the parent amine bytreatment with phosgene and base in an inert solvent such as methylenedichloride or by reacting an amine with its counterpart amine with anacyl amine containing an alternate leaving group formed by reaction ofthat amine with 4-nitrophenylchloroformate in the presence of an aminebase and in an inert solvent.

Details of these methods can be found in Matsuno et al. J Med. Chem.45:3057-66 (2002); Matsuno et al. J. Med. Chem. 45:4513-23 (2002); andand Pandley et al., J. Med. Chem. 45:3772-93 (2002).

Cyclized forms of the ureas may be obtained by treating the formed ureawith dibromo derivatives of the bridge, typically in the presence of astrong base and in an inert aprotic polar solvent.

The ureas may be converted to thioureas by treating with Lawesson'sreagent in the presence of toluene.

For compounds having the moiety Ar¹-L-Ar² is obtained by firstprotecting the amino group of p-hydroxy aniline destined to become Ar¹with a protecting agent such as Boc and then coupling the hydroxy groupof Ar¹ to an aryl alkyl halide. This coupling is conducted in thepresence of strong base and in an aprotic solvent. After deprotection,the urea is formed by reaction with the isoxazole isocyanate. Thesetechniques are exemplified below.

Selected examples of covalent linkages and precursor functional groupswhich yield them are given in the Table entitled “Examples of CovalentLinkages and Precursors Thereof.” Precursor functional groups are shownas electrophilic groups and nucleophilic groups. The functional group onthe organic substance may be attached directly, or attached via anyuseful spacer or linker as defined below. TABLE 1 Examples of CovalentLinkages and Precursors Thereof Covalent Linkage Product ElectrophileNucleophile Carboxamides Activated esters amines/anilines Carboxamidesacyl azides amines/anilines Carboxamides acyl halides amines/anilinesEsters acyl halides alcohols/phenols Esters acyl nitrilesalcohols/phenols Carboxamides acyl nitriles amines/anilines IminesAldehydes amines/anilines Hydrazones aldehydes or ketones HydrazinesOximes aldehydes or ketones Hydroxylamines Alkyl amines alkyl halidesamines/anilines Esters alkyl halides carboxylic acids Thioethers alkylhalides Thiols Ethers alkyl halides alcohols/phenols Thioethers alkylsulfonates Thiols Esters alkyl sulfonates carboxylic acids Ethers alkylsulfonates alcohols/phenols Esters Anhydrides alcohols/phenolsCarboxamides Anhydrides amines/anilines Thiophenols aryl halides ThiolsAryl amines aryl halides Amines Thioethers Azindines Thiols Boronateesters Boronates Glycols Carboxamides carboxylic acids amines/anilinesEsters carboxylic acids Alcohols hydrazines Hydrazides carboxylic acidsN-acylureas or Anhydrides carbodiimides carboxylic acids Estersdiazoalkanes carboxylic acids Thioethers Epoxides Thiols Thioethershaloacetamides Thiols Ammotriazines halotriazines amines/anilinesTriazinyl ethers halotriazines alcohols/phenols Amidines imido estersamines/anilines Ureas Isocyanates amines/anilines Urethanes Isocyanatesalcohols/phenols Thioureas isothiocyanates amines/anilines ThioethersMaleimides Thiols Phosphite esters phosphoramidites Alcohols Silylethers silyl halides Alcohols Alkyl amines sulfonate estersamines/anilines Thioethers sulfonate esters Thiols Esters sulfonateesters carboxylic acids Ethers sulfonate esters Alcohols Sulfonamidessulfonyl halides amines/anilines Sulfonate esters sulfonyl halidesphenols/alcohols

In general, carbon electrophiles are susceptible to attack bycomplementary nucleophiles, including carbon nucleophiles, wherein anattacking nucleophile brings an electron pair to the carbon electrophilein order to form a new bond between the nucleophile and the carbonelectrophile.

Suitable carbon nucleophiles include, but are not limited to alkyl,alkenyl, aryl and alkynyl Grignard, organolithium, organozinc, alkyl-,alkenyl , aryl- and alkynyl-tin reagents (organostannanes), alkyl-,alkenyl-, aryl- and alkynyl-borane reagents (organoboranes andorganoboronates); these carbon nucleophiles have the advantage of beingkinetically stable in water or polar organic solvents. Other carbonnucleophiles include phosphorus ylids, enol and enolate reagents; thesecarbon nucleophiles have the advantage of being relatively easy togenerate from precursors well known to those skilled in the art ofsynthetic organic chemistry. Carbon nucleophiles, when used inconjunction with carbon electrophiles, engender new carbon-carbon bondsbetween the carbon nucleophile and carbon electrophile.

Non-carbon nucleophiles suitable for coupling to carbon electrophilesinclude but are not limited to primary and secondary amines, thiols,thiolates, and thioethers, alcohols, alkoxides, azides, semicarbazides,and the like. These non-carbon nucleophiles, when used in conjunctionwith carbon electrophiles, typically generate heteroatom linkages(C—X—C), wherein X is a hetereoatom, e.g, oxygen or nitrogen.

The term “protecting group” refers to chemical moieties that block someor all reactive moieties and prevent such groups from participating inchemical reactions until the protective group is removed. It ispreferred that each protective group be removable by a different means.Protective groups that are cleaved under totally disparate reactionconditions fulfill the requirement of differential removal. Protectivegroups can be removed by acid, base, and hydrogenolysis. Groups such astrityl, dimethoxytrityl, acetal and t-butyldimethylsilyl are acid labileand may be used to protect carboxy and hydroxy reactive moieties in thepresence of amino groups protected with Cbz groups, which are removableby hydrogenolysis, and Fmoc groups, which are base labile. Carboxylicacid and hydroxy reactive moieties may be blocked with base labilegroups such as, without limitation, methyl, ethyl, and acetyl in thepresence of amines blocked with acid labile groups such as t-butylcarbamate or with carbamates that are both acid and base stable buthydrolytically removable.

Carboxylic acid and hydroxy reactive moieties may also be blocked withhydrolytically removable protective groups such as the benzyl group,while amine groups capable of hydrogen bonding with acids may be blockedwith base labile groups such as Fmoc. Carboxylic acid reactive moietiesmay be protected by conversion to simple ester derivatives asexemplified herein, or they may be blocked with oxidatively-removableprotective groups such as 2,4-dimethoxybenzyl, while co-existing aminogroups may be blocked with fluoride labile silyl carbamates.

Allyl blocking groups are useful in then presence of acid- andbase-protecting groups since the former are stable and can besubsequently removed by metal or pi-acid catalysts. For example, anallyl-blocked carboxylic acid can be deprotected with a Pdo-catalyzedreaction in the presence of acid labile t-butyl carbamate or base-labileacetate amine protecting groups. Yet another form of protecting group isa resin to which a compound or intermediate may be attached. As long asthe residue is attached to the resin, that functional group is blockedand cannot react. Once released from the resin, the functional group isavailable to react.

Typically blocking/protecting groups may be selected from:

Other protecting groups are described in Greene and Wuts, ProtectiveGroups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, N.Y.,1999, which is incorporated herein by reference in its entirety.

Biological Activity

Protein kinases (PKs) play a role in signal transduction pathwaysregulating a number of cellular functions, such as cell growth,differentiation, and cell death. PKs are enzymes that catalyze thephosphorylation of hydroxy groups on tyrosine, serine and threonineresidues of proteins. Abnormal PK activity has been related to disordersranging from relatively non life threatening diseases such as psoriasisto extremely virulent diseases such as glioblastoma (brain cancer). Inaddition, a variety of tumor types have dysfunctional growth factorreceptor tyrosine kinases, resulting in inappropriate mitogenicsignaling. Protein kinases are believed to be involved in many differentcellular signal transduction pathways. In particular, protein tyrosinekinases (PTK) are attractive targets in the search for therapeuticagents, not only for cancer, but also against many other diseases.Blocking or regulating the kinase phosphorylation process in a signalingcascade may help treat conditions such as cancer or inflammatoryprocesses.

Protein tyrosine kinases are a family of tightly regulated enzymes, andthe aberrant activation of various members of the family is one of thehallmarks of cancer. The protein-tyrosine kinase family includes Bcr-Abltyrosine kinase, and can be divided into subgroups that have similarstructural organization and sequence similarity within the kinasedomain. The members of the type III group of receptor tyrosine kinasesinclude the platelet-derived growth factor (PDGF) receptors (PDGFreceptors α and β), colony-stimulating factor (CSF-1) receptor (CSF-1R,c-Fms), FLT-3, and stem cell or steel factor receptor (c-kit).

The compounds, compositions, and methods provided herein are useful tomodulate the activity of kinases including, but not limited to, ERBB2,ABL1, AURKA, CDK2, EGFR, FGFR1, LCK, MAPK14, PDGFR, KDR, ABL1, BRAF,ERBB4, FLT3, KIT, and RAF1. In some embodiments, the compositions andmethods provided herein modulate the activity of a mutant kinase.

Inhibition by the compounds provided herein can be determined using anysuitable assay. In one embodiment, inhibition is determined in vitro. Ina specific embodiment, inhibition is assessed by phosphorylation assays.Any suitable phosphorylation assay can be employed. For example,membrane autophosphorylation assays, receptor autophosphorylation assaysin intact cells, and ELISA's can be employed. See, e.g., Gazit, et al.,J. Med. Chem. (1996) 39:2170-2177, Chapter 18 in CURRENT PROTOCOLS INMOLECULAR BIOLOGY (Ausubel, et al., eds. 2001). Cells useful in suchassays include cells with wildtype or mutated forms. In one embodiment,the wildtype is a kinase that is not constitutively active, but isactivated with upon dimerization. For example, the mutant FLT3 kinase isconstitutively active via internal tandem duplication mutations or pointmutations in the activation domain. Suitable cells include those derivedthrough cell culture from patient samples as well as cells derived usingroutine molecular biology techniques, e.g., retroviral transduction,transfection, mutagenesis, etc. Exemplary cells include Ba/F3 or 32Dc13cells transduced with, e.g., MSCV retroviral constructs FLT3-ITD (Kellyet al., 2002); Molm-13 and Molm14 cell line (Fujisaki Cell Center,Okayama, Japan); HL60 (AML-M3), AML193 (AML-M5), KG-1, KG-1a, CRL-1873,CRL-9591, and THP-1 (American Tissue Culture Collection, Bethesda, Md.);or any suitable cell line derived from a patient with a hematopoieticmalignancy.

In some embodiments, the compounds described herein significantlyinhibit receptor tyrosine kinases. A significant inhibition of areceptor tyrosine kinase activity refers to an IC₅₀ of less than orequal to 100 μM. Preferably, the compound can inhibit activity with anIC₅₀ of less than or equal to 50 μM, more preferably less than or equalto 10 μM, more preferably less than 1 μM, or less than 100 nM, mostpreferably less than 50 nM. Lower IC₅₀'s are preferred because the IC₅₀provides an indication as to the in vivo effectiveness of the compound.Other factors known in the art, such as compound half-life,biodistribution, and toxicity should also be considered for therapeuticuses. Such factors may enable a compound with a lower IC₅₀ to havegreater in vivo efficacy than a compound having a higher IC₅₀Preferably, a compound that inhibits activity is administered at a dosewhere the effective tyrosine phosphorylation, i.e., IC₅₀, is less thanits cytotoxic effects, LD₅₀.

In some embodiments, the compounds selectively inhibit one or morekinases. Selective inhibition of a kinase, such as FLT3, p38 kinase,STK10, MKNK2, Bcr-Abl, c-kit, or PDGFR, is achieved by inhibitingactivity of one kinase, while having an insignificant effect on othermembers of the superfamily.

FLT-3

FLT3 kinase is a tyrosine kinase receptor involved in the regulation andstimulation of cellular proliferation. See e.g., Gilliland et al., Blood100:1532-42 (2002). The FLT3 kinase is a member of the class IIIreceptor tyrosine kinase (RTKIII) receptor family and belongs to thesame subfamily of tyrosine kinases as c-kit, c-fms, and theplatelet-derived growth factor a and B receptors. See e.g., Lyman etal., FLT3 Ligand in THE CYTOKINE HANDBOOK 989 (Thomson et al., eds. 4thEd.) (2003). The FLT3 kinase has five immunoglobulin-like domains in itsextracellular region as well as an insert region of 75-100 amino acidsin the middle of its cytoplasmic domain. FLT3 kinase is activated uponthe binding of the FLT3 ligand, which causes receptor dimerization.Dimerization of the FLT3 kinase by FLT3 ligand activates theintracellular kinase activity as well as a cascade of downstreamsubstrates including Stat5, Ras, phosphatidylinositol-3-kinase (PI3K),PLCγ, Erk2, Akt, MAPK, SHC, SHP2, and SHIP. See e.g., Rosnet et al.,Acta Haematol. 95:218 (1996); Hayakawa et al., Oncogene 19:624 (2000);Mizuki et al., Blood 96:3907 (2000); and Gilliand et al., Curr. Opin.Hematol. 9: 274-81 (2002). Both membrane-bound and soluble FLT3 ligandbind, dimerize, and subsequently activate the FLT3 kinase.

In normal cells, immature hematopoietic cells, typically CD34+ cells,placenta, gonads, and brain express FLT3 kinase. See, e.g., Rosnet, etal., Blood 82:1110-19 (1993); Small et al., Proc. Natl. Acad. Sci.U.S.A. 91:459-63 (1994); and Rosnet et al., Leukemia 10:238-48 (1 996).However, efficient stimulation of proliferation via FLT3 kinasetypically requires other hematopoietic growth factors or interleukins.FLT3 kinase also plays a critical role in immune function through itsregulation of dendritic cell proliferation and dilferentiation. Seee.g., McKenna et al., Blood 95:3489-97 (2000).

Numerous hematologic malignancies express FLT3 kinase, the mostprominent of which is AML. See e.g., Yokota et al., Leukemia 11:1605-09(1997). Other FLT3 expressing malignancies include B-precursor cellacute lymphoblastic leukemias, myelodysplastic leukemias, T-cell acutelymphoblastic leukemias, and chronic myelogenous leukemias. See e.g.,Rasko et al., Leukemia 9:2058-66 (1995).

FLT3 kinase mutations associated with hematologic malignancies areactivating mutations. In other words, the FLT3 kinase is constitutivelyactivated without the need for binding and dimerization by FLT3 ligand,and therefore stimulates the cell to grow continuously.

Several studies have identified inhibitors of FLT3 kinase activity thatalso inhibit the kinase activity of related receptors, e.g., VEGFreceptor (VEGFR), PDGF receptor (PDGFR), and kit receptor kinases. Seee.g., Mendel et al., Clin. Cancer Res. 9:327-37 (2003); O'Farrell etal., Blood 101:3597-605 (2003); and Sun et al., J. Med. Chem. 46:1116-19(2003). Such compounds effectively inhibit FLT3 kinase-mediatedphosphorylation, cytokine production, cellular proliferation, resultingin the induction of apoptosis. See e.g., Spiekermann et al., Blood101:1494-1504 (2003). Moreover, such compounds have potent antitumoractivity in vitro and in vivo.

In some embodiments, the kinase is a class III receptor tyrosine kinase(RTKIII). In other embodiments, the kinase is a tyrosine kinase receptorintimately involved in the regulation and stimulation of cellularproliferation. In still other embodiments, the kinase is a fms-liketyrosine kinase 3 receptor (FLT-3 kinase). In this context, inhibitionand reduction of the activity of FLT-3 kinase refers to a lower level ofmeasured activity relative to a control experiment in which the protein,cell, or subject is not treated with the test compound, whereas anincrease in the activity of FLT-3 kinase refers to a higher level ofmeasured activity relative to a control experiment. In particularembodiments, the reduction or increase is at least 10%. One of skill inthe art will appreciate that reduction or increase in the activity ofFLT-3 kinase of at least 20%, 50%, 75%, 90% or 100% or any integerbetween 10% and 100% may be preferred for particular applications.

Compounds provided herein are useful in treating conditionscharacterized by inappropriate FLT3 activity such as proliferativedisorders. FLT3 activity includes, but is not limited to, enhanced FLT3activity resulting from increased or de novo expression of FLT3 incells, increased FLT3 expression or activity, and FLT3 mutationsresulting in constitutive activation. The existence of inappropriate orabnormal FLT3 ligand and FLT3 levels or activity can be determined usingwell known methods in the art. For example, abnormally high FLT3 levelscan be determined using commercially available ELISA kits. FLT3 levelscan be determined using flow cytometric analysis, immunohistochemicalanalysis, and in situ hybridization techniques.

An inappropriate activation of the FLT3 can be determined by an increasein one or more of the activities occurring subsequent to FLT3 binding:(1) phosphorylation or autophosphorylation of FLT3; (2) phosphorylationof a FLT3 substrate, e.g., Stat5, Ras; (3) activation of a relatedcomplex, e.g., PI3K; (4) activation of an adaptor molecule; and (5)cellular proliferation. These activities are readily measured by wellknown methods in the art.

Formulations

The compounds described herein can be used to prepare a medicament, suchas by formulation into pharmaceutical compositions for administration toa subject using techniques generally known in the art. A summary of suchpharmaceutical compositions may be found, for example, in Remington'sPharmaceutical Sciences, Mack Publishing Co., Easton, Pa. The compoundsof the invention can be used singly or as components of mixtures.Preferred forms of the compounds are those for systemic administrationas well as those for topical or transdermal administration. Formulationsdesigned for timed release are also within the scope of the invention.Formulation in unit dosage form is also preferred for the practice ofthe invention.

In unit dosage form, the formulation is divided into unit dosescontaining appropriate quantities of one or more compounds. The unitdosage may be in the form of a package containing discrete quantities ofthe formulation. Non-limiting examples are packeted tablets or capsules,and powders in vials or ampoules.

The compounds described herein may be labeled isotopically (e.g. with aradioisotope) or by any other means, including, but not limited to, theuse of chromophores or fluorescent moieties, bioluminescent labels, orchemiluminescent labels. The compositions may be in conventional forms,either as liquid solutions or suspensions, solid forms suitable forsolution or suspension in a liquid prior to use, or as emulsions.Suitable excipients or carriers are, for example, water, saline,dextrose, glycerol, alcohols, aloe vera gel, allantoin, glycerin,vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristylpropionate, and the like. Of course, these compositions may also containminor amounts of nontoxic, auxiliary substances, such as wetting oremulsifying agents, pH buffering agents, and so forth.

Methods for the preparation of compositions comprising the compoundsdescribed herein include formulating the derivatives with one or moreinert, pharmaceutically acceptable carriers to form either a solid orliquid. Solid compositions include, but are not limited to, powders,tablets, dispersible granules, capsules, cachets, and suppositories.Liquid compositions include solutions in which a compound is dissolved,emulsions comprising a compound, or a solution containing liposomes,micelles, or nanoparticles comprising a compound as disclosed herein.

A carrier of the invention can be one or more substances which alsoserve to act as a diluent, flavoring agent, solubilizer, lubricant,suspending agent, binder, or tablet disintegrating agent. A carrier canalso be an encapsulating material.

In powder forms of the invention's compositions, the carrier ispreferably a finely divided solid in powder form which is interdispersedas a mixture with a finely divided powder from of one or more compound.In tablet forms of the compositions, one or more compounds is intermixedwith a carrier with appropriate binding properties in suitableproportions followed by compaction into the shape and size desired.Powder and tablet form compositions preferably contain between about 5to about 70% by weight of one or more compound. Carriers that may beused in the practice of the invention include, but are not limited to,magnesium carbonate, magnesium stearate, talc, lactose, sugar, pectin,dextrin, starch, tragacanth, methyl cellulose, sodium carboxymethylcellulose, a low-melting wax, cocoa butter, and the like.

The compounds of the invention may also be encapsulated ormicroencapsulated by an encapsulating material, which may thus serve asa carrier, to provide a capsule in which the derivatives, with orwithout other carriers, is surrounded by the encapsulating material. Inan analogous manner, cachets comprising one or more compounds are alsoprovided by the instant invention. Tablet, powder, capsule, and cachetforms of the invention can be formulated as single or unit dosage formssuitable for administration, optionally conducted orally.

In suppository forms of the compositions, a low-melting wax such as, butnot limited to, a mixture of fatty acid glycerides, optionally incombination with cocoa butter is first melted. One or more compounds arethen dispersed into the melted material by, as a non-limiting example,stirring. The non-solid mixture is then placed into molds as desired andallowed to cool and solidify.

Non-limiting compositions in liquid form include solutions suitable fororal or parenteral administration, as well as suspensions and emulsionssuitable for oral administration. Sterile aqueous based solutions of oneor more compounds, optionally in the presence of an agent to increasesolubility of the derivative(s), are also provided. Non-limitingexamples of sterile solutions include those comprising water, ethanol,and/or propylene glycol in forms suitable for parenteral administration.A sterile solution of the invention may be prepared by dissolving one ormore compounds in a desired solvent followed by sterilization, such asby filtration through a sterilizing membrane filter as a non-limitingexample. In another embodiment, one or more compounds are dissolved intoa previously sterilized solvent under sterile conditions.

A water based solution suitable for oral administration can be preparedby dissolving one or more compounds in water and adding suitableflavoring agents, coloring agents, stabilizers, and thickening agents asdesired. Water based suspensions for oral use can be made by dispersingone or more compounds in water together with a viscous material such as,but not limited to, natural or synthetic gums, resins, methyl cellulose,sodium carboxymethyl cellulose, polyvinylpyrrolidone, and othersuspending agents known to the pharmaceutical field.

In therapeutic use, the compounds of the invention are administered to asubject at dosage levels of from about 0.5 mg/kg to about 8.0 mg/kg ofbody weight per day. For example, a human subject of approximately 70kg, this is a dosage of from 35 mg to 560 mg per day. Such dosages,however, may be altered depending on a number of variables, not limitedto the activity of the compound used, the condition to be treated, themode of administration, the requirements of the individual subject, theseverity of the condition being treated, and the judgment of thepractitioner.

The foregoing ranges are merely suggestive, as the number of variablesin regard to an individual treatment regime is large, and considerableexcursions from these recommended values are not uncommon.

Methods of Use

By modulating kinase activity, the compounds disclosed herein can beused to treat a variety of diseases. Suitable conditions characterizedby undesirable protein-kinase activity can be treated by the compoundspresented herein. As used herein, the term “condition” refers to adisease, disorder, or related symptom where inappropriate kinaseactivity is present. In some embodiments, these conditions arecharacterized by aggressive neovasculaturization including tumors,especially acute myelogenous leukemia (AML), B-precursor cell acutelymphoblastic leukemias, myelodysplastic leukemias, T-cell acutelymphoblastic leukemias, and chronic myelogenous leukemias (CMLs). Insome embodiments, a FLT3 modulating compounds may be used to treattumors. The ability of compounds that inhibit FLT3 kinase activity totreat tumors has been established. Compounds having this propertyinclude SU5416 (Sugen), PKC412 (Novartis), GTP-14564 and CT53518(Millennium). See e.g., Giles et al., Blood 102:795-801 (2003); Weisberget al., Cancer Cell 1:433-43 (2002); Murata et al., J. Biol. Chem.278:32892-98 (2003); and Kelly et al., Cancer Cell 1:421-32 (2002).

Compounds presented herein are useful in the treatment of a variety ofbiologically aberrant conditions or disorders related to tyrosine kinasesignal transduction. Such disorders pertain to abnormal cellproliferation, differentiation, and/or metabolism. Abnormal cellproliferation may result in a wide array of diseases, including thedevelopment of neoplasia such as carcinoma, sarcoma, leukemia,glioblastoma, hemangioma, psoriasis, arteriosclerosis, arthritis anddiabetic retinopathy (or other disorders related to uncontrolledangiogenesis and/or vasculogenesis).

In various embodiments, compounds presented herein regulate, modulate,and/or inhibit disorders associated with abnormal cell proliferation byaffecting the enzymatic activity of one or more tyrosine kinases andinterfering with the signal transduced by said kinase. Moreparticularly, the present invention is directed to compounds whichregulate, modulate said kinase mediated signal transduction pathways asa therapeutic approach to cure leukemia and many kinds of solid tumors,including but not limited to carcinoma, sarcoma, erythroblastoma,glioblastoma, meningioma, astrocytoma, melanoma and myoblastoma.Indications may include, but are not limited to brain cancers, bladdercancers, ovarian cancers, gastric cancers, pancreas cancers, coloncancers, blood cancers, lung cancers and bone cancers.

In other embodiments, compounds herein are useful in the treatment ofcell proliferative disorders including cancers, blood vesselproliferative disorders, fibrotic disorders, and mesangial cellproliferative disorders. Blood vessel proliferation disorders refer toangiogenic and vasculogenic disorders generally resulting in abnormalproliferation of blood vessels. The formation and spreading of bloodvessels, or vasculogenesis and angiogenesis, respectively, playimportant roles in a variety of physiological processes such asembryonic development, corpus luteum formation, wound healing and organregeneration. They also play a pivotal role in cancer development. Otherexamples of blood vessel proliferation disorders include arthritis,where new capillary blood vessels invade the joint and destroycartilage, and ocular diseases, like diabetic retinopathy, where newcapillaries in the retina invade the vitreous, bleed and causeblindness. Conversely, disorders related to the shrinkage, contractionor closing of blood vessels, such as restenosis, are also implicated.

Fibrotic disorders refer to the abnormal formation of extracellularmatrix. Examples of fibrotic disorders include hepatic cirrhosis andmesangial cell proliferative disorders. Hepatic cirrhosis ischaracterized by the increase in extracellular matrix constituentsresulting in the formation of a hepatic scar. Hepatic cirrhosis cancause diseases such as cirrhosis of the liver. An increasedextracellular matrix resulting in a hepatic scar can also be caused byviral infection such as hepatitis. Lipocytes appear to play a major rolein hepatic cirrhosis. Other fibrotic disorders implicated includeatherosclerosis (see, below).

Mesangial cell proliferative disorders refer to disorders brought aboutby abnormal proliferation of mesangial cells. Mesangial proliferativedisorders include various human renal diseases, such asglomerulonephritis, diabetic nephropathy, malignant nephrosclerosis,thrombotic microangiopathy syndromes, transplant rejection, andglomerulopathies. The cell proliferative disorders which are indicationsof the present invention are not necessarily independent. For example,fibrotic disorders may be related to, or overlap, with blood vesselproliferative disorders. For example, atherosclerosis results, in part,in the abnormal formation of fibrous tissue within blood vessels.

Compounds of the invention can be-administered to a subject upondetermination of the subject as having a disease or unwanted conditionthat would benefit by treatment with said derivative. The determinationcan be made by medical or clinical personnel as part of a diagnosis of adisease or condition in a subject. Non-limiting examples includedetermination of a risk of acute myelogenous leukemia (AML), B-precursorcell acute lymphoblastic leukemias, myelodysplastic leukemias, T-cellacute lymphoblastic leukemias, and chronic myelogenous leukemias (CMLs).

The methods of the invention can comprise the administration of aneffective amount of one or more compounds as disclosed herein,optionally in combination with one or more other active agents for thetreatment of a disease or unwanted condition as disclosed herein. Thesubject is preferably human, and repeated administration over time iswithin the scope of the present invention.

The present invention thus also provides compounds described above andtheir salts or solvates and pharmaceutically acceptable salts orsolvates thereof for use in the prevention or treatment of disordersmediated by aberrant protein tyrosine kinase activity such as humanmalignancies and the other disorders mentioned above. The compounds ofthe present invention are especially useful for the treatment ofdisorders caused by aberrant kinase activity such as breast, ovarian,gastric, pancreatic, non-small cell lung, bladder, head and neckcancers, and psoriasis. The cancers include hematologic cancers, forexample, acute myelogenous leukemia (AML), B-precursor cell acutelymphoblastic leukemias, myelodysplastic leukemias, T-cell acutelymphoblastic leukemias, and chronic myelogenous leukemias (CMLs).

A further aspect of the invention provides a method of treatment of ahuman or animal subject suffering from a disorder mediated by aberrantprotein tyrosine kinase activity, including susceptible malignancies,which comprises administering to the subject an effective amount of acompound described above or a pharmaceutically acceptable salt orsolvate thereof.

A further aspect of the present invention provides the use of a compounddescribed above, or a pharmaceutically acceptable salt or solvatethereof, in the preparation of a medicament for the treatment of cancerand malignant tumors. The cancer can be stomach, gastric, bone, ovary,colon, lung, brain, larynx, lymphatic system, genitourinary tract,ovarian, squamous cell carcinoma, astrocytoma, Kaposi's sarcoma,glioblastoma, lung cancer, bladder cancer, head and neck cancer,melanoma, ovarian cancer, prostate cancer, breast cancer, small-celllung cancer, leukemia, acute myelogenous leukemia (AML), B-precursorcell acute lymphoblastic leukemias, myelodysplastic leukemias, T-cellacute lymphoblastic leukemias, and chronic myelogenous leukemias (CMLs),glioma, colorectal cancer, genitourinary cancer gastrointestinal cancer,or pancreatic cancer.

In accordance with the present invention, compounds provided herein areuseful for preventing and treating conditions associated with ischemiccell death, such as myocardial infarction, stroke, glaucoma, and otherneurodegenerative conditions. Various neurodegenerative conditions whichmay involve apoptotic cell death, include, but are not limited to,Alzheimer's Disease, ALS and motor neuron degeneration, Parkinson'sdisease, peripheral neuropathies, Down's Syndrome, age related maculardegeneration (ARMD), traumatic brain injury, spinal cord injury,Huntington's Disease, spinal muscular atrophy, and HIV encephalitis. Thecompounds described in detail above can be used in methods andcompositions for imparting neuroprotection and for treatingneurodegenerative diseases.

The compounds described herein, can be used in a pharmaceuticalcomposition for the prevention and/or the treatment of a conditionselected from the group consisting of arthritis (includingosteoarthritis, degenerative joint disease, spondyloarthropathies, goutyarthritis, systemic lupus erythematosus, juvenile arthritis andrheumatoid arthritis), common cold, dysmenorrhea, menstrual cramps,inflammatory bowel disease, Crohn's disease, emphysema, acuterespiratory distress syndrome, asthma, bronchitis, chronic obstructivepulmonary disease, Alzheimer's disease, organ transplant toxicity,cachexia, allergic reactions, allergic contact hypersensitivity, cancer(such as solid tumor cancer including colon cancer, breast cancer, lungcancer and prostrate cancer; hematopoietic malignancies includingleukemias and lymphomas; Hodgkin's disease; aplastic anemia, skin cancerand familiar adenomatous polyposis), tissue ulceration, peptic ulcers,gastritis, regional enteritis, ulcerative colitis, diverticulitis,recurrent gastrointestinal lesion, gastrointestinal bleeding,coagulation, anemia, synovitis, gout, ankylosing spondylitis,restenosis, periodontal disease, epidermolysis bullosa, osteoporosis,atherosclerosis (including atherosclerotic plaque rupture), aorticaneurysm (including abdominal aortic aneurysm and brain aorticaneurysm), periarteritis nodosa, congestive heart failure, myocardialinfarction, stroke, cerebral ischemia, head trauma, spinal cord injury,neuralgia, neurodegenerative disorders (acute and chronic), autoimmunedisorders, Huntington's disease, Parkinson's disease, migraine,depression, peripheral neuropathy, pain (including low back and neckpain, headache and toothache), gingivitis, cerebral amyloid angiopathy,nootropic or cognition enhancement, amyotrophic lateral sclerosis,multiple sclerosis, ocular angiogenesis, corneal injury, maculardegeneration, conjunctivitis, abnormal wound healing, muscle or jointsprains or strains, tendonitis, skin disorders (such as psoriasis,eczema, scleroderma and dermatitis), myasthenia gravis, polymyositis,myositis, bursitis, burns, diabetes (including types I and II diabetes,diabetic retinopathy, neuropathy and nephropathy), tumor invasion, tumorgrowth, tumor metastasis, corneal scarring, scleritis, immunodeficiencydiseases (such as AIDS in humans and FLV, FIV in cats), sepsis,premature labor, hypoprothrombinemia, hemophilia, thyroiditis,sarcoidosis, Behcet's syndrome, hypersensitivity, kidney disease,Rickettsial infections (such as Lyme disease, Erlichiosis), Protozoandiseases (such as malaria, giardia, coccidia), reproductive disorders,and septic shock, arthritis, fever, common cold, pain and cancer in amammal, preferably a human, cat, livestock or a dog, comprising anamount of a compound described herein or a pharmaceutically acceptablesalt thereof effective in such prevention and/or treatment optionallywith a pharmaceutically acceptable carrier.

A further aspect of the present invention provides the use of a compounddescribed above, or a pharmaceutically acceptable salt thereof, in thepreparation of a medicament for the treatment of psoriasis.

As one of skill in the art will recognize, the compounds can beadministered before, during or after the occurrence of a condition or adisease, and the timing of administering the composition containing acompound can vary. Thus, for example, the compounds can be used as aprophylactic and can be administered continuously to subjects with apropensity to conditions and diseases in order to prevent the occurrenceof the disorder. The compounds and compositions can be administered to asubject during or as soon as possible after the onset of the symptoms.The administration of the compounds can be initiated within the first 48hours of the onset of the symptoms, preferably within the first 48 hoursof the onset of the symptoms, more preferably within the first 6 hoursof the onset of the symptoms, and most preferably within 3 hours of theonset of the symptoms. The initial administration can be via any routepractical, such as, for example, an intravenous injection, a bolusinjection, infusion over 5 min. to about 5 hours, a pill, a capsule,transdermal patch, buccal delivery, and the like, or a combinationthereof. A compound is preferably administered as soon as is practicableafter the onset of a condition or a disease is detected or suspected,and for a length of time necessary for the treatment of the disease,such as, for example, from about 1 month to about 3 months. As one ofskill in the art will recognize, the length of treatment can vary foreach subject, and the length can be determined using the known criteria.For example, the compound or a formulation containing the compound canbe administered for at least 2 weeks, preferably about 1 month to about5 years, and more preferably from about 1 month to about 3 years.

Kits/Articles of Manufacture

For use in the therapeutic applications described herein, kits andarticles of manufacture are also within the scope of the invention. Suchkits can comprise a carrier, package, or container that iscompartmentalized to receive one or more containers such as vials,tubes, and the like, each of the container(s) comprising one of theseparate elements to be used in a method of the invention. Suitablecontainers include, for example, bottles, vials, syringes, and testtubes. The containers can be formed from a variety of materials such asglass or plastic.

For example, the container(s) can comprise one or more compounds of theinvention, optionally in a composition or in combination with anotheragent as disclosed herein. The container(s) optionally have a sterileaccess port (for example the container can be an intravenous solutionbag or a vial having a stopper pierceable by a hypodermic injectionneedle). Such kits optionally comprising a compound with an identifyingdescription or label or instructions relating to its use in the methodsof the present invention.

A kit of the invention will typically may comprise one or moreadditional containers, each with one or more of various materials (suchas reagents, optionally in concentrated form, and/or devices) desirablefrom a commercial and user standpoint for use of a compound of theinvention. Non-limiting examples of such materials include, but notlimited to, buffers, diluents, filters, needles, syringes; carrier,package, container, vial and/or tube labels listing contents and/orinstructions for use, and package inserts with instructions for use. Aset of instructions will also typically be included.

A label can be on or associated with the container. A label can be on acontainer when letters, numbers or other characters forming the labelare attached, molded or etched into the container itself; a label can beassociated with a container when it is present within a receptacle orcarrier that also holds the container, e.g., as a package insert. Alabel can be used to indicate that the contents are to be used for aspecific therapeutic application. The label can also indicate directionsfor use of the contents, such as in the methods described herein.

The terms “kit” and “article of manufacture” may be used as synonyms.

EXAMPLES

The present invention is further illustrated by the following examples,which should not be construed as limiting in any way. The experimentalprocedures to generate the data shown are discussed in more detailbelow. For all formulations herein, multiple doses may be proportionallycompounded as is known in the art.

The invention has been described in an illustrative manner, and it is tobe understood that the terminology used is intended to be in the natureof description rather than of limitation. Thus, it will be appreciatedby those of skill in the art that conditions such as choice of solvent,temperature of reaction, volumes, reaction time may vary while stillproducing the desired compounds. In addition, one of skill in the artwill also appreciate that many of the reagents provided in the followingexamples may be substituted with other suitable reagents. See, e.g.,Smith & March, Advanced Organic Chemistry, 5^(th) ed. (2001).

Example A Synthesis of Isoxazole-Amides

Compounds A1 through A240 are synthesized by methods known in the art ordescribed herein. The structures are shown below in Table A: TABLE A NO.STRUCTURE A1

A2

A3

A4

A5

A6

A7

A8

A9

A10

A11

A12

A13

A14

A15

A16

A17

A18

A19

A20

A21

A22

A23

A24

A25

A26

A27

A28

A29

A30

A31

A32

A33

A34

A35

A36

A37

A38

A39

A40

A41

A42

A43

A44

A45

A46

A47

A48

A49

A50

A51

A52

A53

A54

A55

A56

A57

A58

A59

A60

A61

A62

A63

A64

A65

A66

67

A68

A69

A70

A71

A72

A73

A74

A75

A76

A77

A78

A79

A80

A81

A82

A83

A84

A85

A86

A87

A88

A89

A90

A91

A92

A93

A94

A95

A96

A97

A98

A99

A100

A101

A102

A103

A104

A105

A106

A107

A108

A109

A110

A111

A112

A113

A114

A115

A116

A117

A118

A119

A120

A121

A122

A123

A124

A125

A126

A127

A128

A129

A130

A131

A132

A133

A134

A135

A136

A137

A138

A139

A140

A141

A142

A143

A144

A145

A146

A147

A148

A149

A150

A151

A152

A153

A154

A155

A156

A157

A158

A159

A160

A161

A162

A163

A164

A165

A166

A167

A168

A169

A170

A171

A172

A173

A174

A175

A176

A177

A178

A179

A180

A181

A182

A183

A184

A185

A186

A187

A188

A189

A190

A191

A192

A193

A194

A195

A196

A197

A198

A199

A200

A201

202

A203

A204

A205

A206

A207

A208

A209

A210

A211

A212

A213

A214

A215

A216

A217

A218

A219

A220

A221

A222

A223

A224

A225

A226

A227

A228

A229

A230

A231

A232

A233

A234

A235

A236

A237

A238

A239

A240

Example B Exemplary Synthesis of Isoxazole-Amides

In a 40 mL vial, 1 mL of thionyl chloride was added to 0.2 mmolpara-substituted phenylacetic acid. The vial was capped and stirred at80° C. for approximately three hours. The completion of the reaction waschecked by TLC. The excess thionyl chloride was removed in vacuo. Theresidue was dissolved in dichloromethane and added to a mixture of3-tert-butyl-isoxazol-5-ylamine (0.2 mmol) and DIEA (0.2 mmol). Thereaction was stirred overnight at 45° C. The solvent was removed undervacuum and the product was purified by HPLC.

Synthesis of Compound B1:N-(3-tert-butylisoxazol-5-yl)-2-(4-(benzyloxy)phenyl)acetamide

(4-Benzyloxy-phenyl)-acetic acid (50 mg, 0.2 mmol, 1 eq) was stirredwith 1 mL of thionyl chloride at 80° C. for approximately three hours.The completion of the reaction was checked by TLC. Excess thionylchloride was removed in vacuo, the residue was dissolved indichloromethane and added to a mixture of3-tert-butyl-isoxazol-5-ylamine (28mg, 0.2 mmol, 1 eq) and DIEA (35 μL,0.2 mmol, 1 eq). The reaction was stirred overnight at 45° C. Thesolvent was removed and the product purified by HPLC. Yield: 42 mg(57%), LC/MS [MH⁺]365.

Compounds B2 through B16 were synthesized in a manner analogous toCompound B1 using similar starting materials and reagents. Thestructures are shown below in Table B: TABLE B NO. CHEMICAL STRUCTURE B1

B2

B3

B4

B5

B6

B7

B8

B9

B10

B11

B12

B13

B14

B15

B16

Example C Synthesis of thiazole-amides Synthesis of Compound C1:2-(4-(benzyloxy)phenyl)-N-(5-methylthiazol-2-yl)acetamide

Compound C1 was prepared in strict analogy to compound B1 using2-amino-5-methylthiazole as starting material instead of3-tert-butyl-isoxazol-5-ylamine.

Compounds C2 through C6 were synthesized in a manner analogous toCompound C1 using similar starting materials and reagents. Thestructures are shown below in Table C: TABLE C NO. CHEMICAL STRUCTURE C1

C2

C3

C4

C5

C6

Example E Synthesis of Di-Phenyl Ureas Synthesis of Compound E1:2-(4-Fluoro-phenyl)-N-(5-methyl-2-phenyl-2H-pyrazol-3-)-acetamide

Compound E1 was prepared in strict analogy to compound B1 using5-methyl-2-phenyl-2H-pyrazol-3-ylamine and 4-fluorophenylacetic acid asstarting materials.

Compounds E2 through E20 were synthesized in a manner analogous toCompound E1 using similar starting materials and reagents. Thestructures are shown below in Table E: TABLE E NO. CHEMICAL STRUCTURE E1

E2

E3

E4

E5

E6

E7

E8

E9

E10

E11

E12

E13

E14

E15

E16

E17

E18

E19

E20

Example F Synthesis of Isoxazole-Bis-Amides

In a vial thionyl chloride was added to a para-substituted phenylaceticacid. The vial was capped and stirred at 80° C. for approximately threehours. The completion of the reaction was checked by TLC, and the excessthionyl chloride removed in vacuo. The residue was dissolved indichloromethane and added to a mixture 5-tert-butyl-isoxazol-3-ylamineand DIEA. The reaction was stirred overnight at 45° C. The solvent wasremoved under vacuum and the product was purified by HPLC.

For the case of R═NO₂, reduction to the amine was carried out prior toreaction with an activated carboxylic acid. 1.5 gm of1-(5-tert-butyl-isoxazol-3-yl)-3-(4-nitro-phenyl)-amide was dissolved in50 ml THF and 0.1 g of 10% Pd/C is added. The solution was stirred underhydrogen at 50 psi. for 24 hours then filtered through a Celite pad. Theorganic solvent was evaporated under vacuum and the resulting residuewas triturated with ethyl acetate.

1 equivalent of the carboxylic acid and 1.1 equivalent of CDI weredissolved in dry DMF and stirred at 40° C. for 2 h, then 1 equivalent ofthe substituted aniline was added. The reaction mixture was stirred at40° C. overnight and the final product was purified by preparative HPLC.

Alternatively, 1 equivalent of the carboxylic acid and 1.1 equivalent ofthionyl chloride were heated in a sealed tube at 50 C for 3 h. Theexcess thionyl chloride was evaporated, 1 equivalent of aniline in DMFwas added, and the solution stirred at room temperature for 8 h. Thefinal product was purified by preparative HPLC.

Compounds F1 through F5 are synthesized in a manner analogous to thoseshown above using similar starting materials and reagents. Thestructures are shown below in Table F: TABLE F NO. CHEMICAL STRUCTURE F1

F2

F3

F4

F5

Binding Constant (K_(d)) Measurements for Small-Molecule-KinaseInteractions

Methods for measuring binding affinities for interactions between smallmolecules and kinases including FLT3, c-KIT, ABL(T3341) [a.k.a.ABL(T315I)], VEGFR2 (a.k.a. KDR), and EGFR are described in detail inU.S. application Ser. No. 10/873,835, which is incorporated by referenceherein in its entirety. The components of the assays include humankinases expressed as fusions to T7 bacteriophage particles andimmobilized ligands that bind to the ATP site of the kinases. For theassay, phage-displayed kinases and immobilized ATP site ligands arecombined with the compound to be tested. If the test compound binds thekinase it competes with the immobilized ligand and prevents binding tothe solid support. If the compound does not bind the kinase,phage-displayed proteins are free to bind to the solid support throughthe interaction between the kinase and the immobilized ligand. Theresults are read out by quantitating the amount of fusion protein boundto the solid support, which is accomplished by either traditional phageplaque assays or by quantitative PCR (qPCR) using the phage genome as atemplate. To determine the affinity of the interactions between a testmolecule and a ,kinase, the amount of phage-displayed kinase bound tothe solid support is quantitated as a function of test compoundconcentration. The concentration of test molecule that reduces thenumber of phage bound to the solid support by 50% is equal to the K_(d)for the interaction between the kinase and the test molecule. Typically,data are collected for twelve concentrations of test compound and, theresultant binding curve is fit to a non-cooperative binding isotherm tocalculate K_(d).

Described in the exemplary assays below is data from binding withvarying kinases. Binding values are reported as follows “+” forrepresentative compounds exhibiting a binding dissociation constant (Kd)of 10,000 nM or higher; “++”for representative compounds exhibiting a Kdof 1,000 nM to 10,000 nM; “+++”for representative compounds exhibiting aKd of 100 nM to 1,000 nM; and “++++”for representative compoundsexhibiting a Kd of less than 100 nM. The term “ND” representsnon-determined values.

The Affinity of the Compounds for FLT3

The ability of FLT3 kinase inhibitors to inhibit cellular proliferationwas also examined. MV4:11 was a cell line derived from a patient withacute myelogenous leukemia. It expressed a mutant FLT3 protein that wasconstitutively active. MV4:11 cells were grown in the presence ofcandidate FLT3 inhibitor molecules, resulting in significantly decreasedproliferation of the leukemia-derived cells in the presence of compound.Inhibition of FLT3 kinase activity prevented proliferation of thesecells, and thus the MV4:11 cell line can be used a model for cellularactivity of small molecule inhibitors of FLT3.

FLT3 Assay Using MV4,11 Cells

MV4,11 cells were grown in an incubator @ 37° C. in 5% CO₂ in Medium 2(RPM 10% FBS, 4 mM glutamine, Penn/Strep). The cells were counted dailyand the cell density was kept between 1e5 and 8e5 cells/ml.

Day One: Enough cells were harvested for experiments to be conducted in50 ml conical tubes. The harvested cells were spun at 500 g for 5 min at4° C., the supernatant was then aspirated and the cells were resuspendedin the starting volume of 1× PBS. The cells were again spun at 500 g for5 min at 4° C. and the supernatant again aspirated. The cells were thenresuspended in medium 3 (DMEM w/glut, 10% FBS, Penn/Strep) to a densityof 4e5 cells/ml and incubated @ 37° C. in 5% CO₂ O/N.

Day Two: The cells were counted and enough medium 3 was added todecrease density to 2e5 cells/ml. 50 ul (10,000 cells) was aliquotedinto each well of a 96 well optical plate using multichannel pipetman.The compound plate was then set up by aliquoting 3 μl of negativecontrol (DMSO) into column 1 of a 96 well 300 ul polypropylene plate,aliquoting 3 μl of positive control (10 mM AB20121) into column 12 ofplate, and aliquoting 3 μl of appropriate compounds from serialdilutions into columns 2-11. To each well, 150 μl of Medium 3 was addedand 50 μl of compound/medium mixture from compound plate into rows ofoptical plate in duplicate. The cells were then incubated @ 37° C. in 5%CO₂ for 3 days.

Day Five: MTS was thawed in a H₂O bath. 20 μl of MTS was added to eachwell of optical plate and the cells were incubated @ 37° C. in 5% CO₂for 2 hours. The plate was then placed on a plate shaker for 30 secondson high speed.

Data for some of the compounds is provided below: Binding Cell CompoundAssay: FLT Assay: CS Structure 3(DKIN) 0001: IC50

++++ ND

++++ ++++

++++ ND

++++ ND

++++ ND Binding Compound Assay: FLT Structure 3(DKIN)

++

++

++

+++

+++ Binding Compound Assay: FLT Structure 3(DKIN)

+

+

+

+

+

+ Binding Cell Compound Assay: FLT Assay: CS Structure 3(DKIN) 0001:IC50

+++ ND

+ ++

++ ++

+ +

+ +

+ ++ Binding Cell Compound Assay: FLT Assay: CS

+ +++

+ +++

+ +

++ ++ Binding Cell Cell Cell Binding Compound Assay: FLT Assay: CSAssay: CS Assay: CS Assay: FLT Structure 3(DKIN) 0001: IC50 0005: IC500002: IC50 3(JMminus)

ND +++ ND + ++++

ND ++++ ND + ++++

ND ++++ ND + ++++

ND ++++ ND + ++++

ND ++ ND + +++

ND ++++ ND + ++++

All references cited herein, including patents, patent applications, andpublications, are herby incorporated by reference in their entireties,whether previously specifically incorporated or not.

Having now fully described this invention, it will be appreciated bythose skilled in the art that the same can be performed within a widerange of equivalent parameters, concentrations, and conditions withoutdeparting from the spirit and scope of the invention and without undueexperimentation.

While this invention has been described in connection with specificembodiments thereof, it will be understood that it is capable of furthermodifications. This application is intended to cover any variations,uses, or adaptations of the invention following, in general, theprinciples of the invention and including such departures from thepresent disclosure as come within known or customary practice within theart to which the invention pertains and as may be applied to theessential features hereinbefore set forth.

1. A method of modulating flt-3 kinase, said method comprisingadministering an effective amount of a compound corresponding to Formula(IA):

wherein: M is substituted or unsubstituted heteroaryl, or substituted orunsubstituted aryl; N is a substituted or unsubstituted aryl, orsubstituted or unsubstituted hetroaryl; and K is

Y is O or S; each R_(k) is independently H, halogen, substituted orunsubstituted alkyl, —OH, substituted or unsubstituted alkoxy, —OC(O)R₂,—NO₂, —N(R₂)₂, —SR₂, —C(O)R₂, —C(O)₂R₂, —C(O)N(R₂)₂, or —N(R₂)C(O)R₂,each R₂ is independently H, substituted or unsubstituted alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; or wherein two R₂ groups are linked togetherby an optionally substituted alkylene; and each n is independently 0, 1,2, 3 or 4; or an active metabolite, or a pharmaceutically acceptableprodrug, isomer, pharmaceutically acceptable salt or solvate thereof. 2.The method of claim 1, wherein said compound corresponds to Formula(IB):

wherein: each Z is independently C, CR₃, N, NR₃, O, or S, provided thatno more than two Z's are heteroatoms and wherein no two adjacent Z's areO or S, where R₃ is H, substituted or unsubstituted alkyl, substitutedor unsubstituted cycloalkyl, substituted or unsubstituted heteroaryl, orsubstituted or unsubstituted aryl; and each R₁ is independently H,halogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR_(c) —OH, —OC(O)R_(c),—NO₂, —N(R_(c))₂, —SR_(c), S(O)_(j)R_(c) where j is 1 or 2,—NR_(c)C(O)R_(c), —C(O)N(R_(c))₂, C(O)₂R_(c), or —C(O)R_(c); or twoadjacent R₁'s, are taken together to form a substituted or unsubstitutedaryl or heteroaryl, where each R_(c) is independently H, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.
 3. The method of claim 2, wherein said compound correspondsto Formula (I):


4. The method of claim 3, wherein said compound corresponds to Formula(II):


5. The method of claim 4, wherein said compound corresponds to Formula(III):

wherein Z₁ is CR₃ or N; and Z₂ is O or S.
 6. The method of claim 5,wherein said compound is selected from the group consisting of:


7. The method of claim 5, wherein said compound corresponds to Formula(IV):

wherein: each R₁ is independently H, halogen, substituted orunsubstituted alkyl, —O(substituted or unsubstituted alkyl),—O(substituted or unsubstituted alkenyl), —NR_(c)C(O)O(substituted orunsubstituted alkyl), —NR_(c)C(O) (substituted or unsubstituted alkyl),—NR_(c)C(O)(substituted or unsubstituted alkenyl),—C(O)NR_(c)(substituted or unsubstituted alkyl), —C(O)NR_(c)(substitutedor unsubstituted alkenyl), —NO₂, —S(═O)R_(c), —SR_(c), C(O)₂R_(c), or—C(O)R_(c); and each R₂ is independently H or substituted orunsubstituted alkyl.
 8. The method of claim 7, wherein said compoundcorresponds to Formula (V):


9. The method of claim 8, wherein said compound is selected from thegroup consisting of:


10. The method of claim 4, wherein said compound corresponds to Formula(VI):

wherein Z₁ is O or S; and Z₂ is CR₃ or N.
 11. The method of claim 10,wherein said compound corresponds to Formula (VII):

wherein: each R₁ is independently H, halogen, substituted orunsubstituted alkyl, —O(substituted or unsubstituted alkyl),—O(substituted or unsubstituted alkenyl), —NR_(c)C(O)O(substituted orunsubstituted alkyl), —NR_(c)C(O) (substituted or unsubstituted alkyl),—NR_(c)C(O)(substituted or unsubstituted alkenyl),—C(O)NR_(c)(substituted or unsubstituted alkyl), —C(O)NR_(c)(substitutedor unsubstituted alkenyl), —NO₂, —S(═O)R_(c), —SR_(c), C(O)₂R_(c), or—C(O)R_(c); and each R₂ is independently H or substituted orunsubstituted alkyl.
 12. The method of claim 10, wherein said compoundcorresponds to Formula (VIII):


13. The method of claim 12, wherein said compound is selected from thegroup consisting of:


14. The method of claim 5, wherein said compound corresponds to Formula(IX):

wherein: L is a linker selected from the group consisting of a covalentbond, substituted or unsubstituted alkenylene, substituted orunsubstituted alkylene, —C(O)NH—, —C(O)—, —NH—, —O—, —S—, —O(substitutedor unsubstituted alkylene)-, —N(substituted or unsubstituted alkylene)-,—C(O)NH(substituted or unsubstituted alkylene)-, —C(O)NH(substituted orunsubstituted alkenylene)- —NHC(O)(substituted or unsubstitutedalkylene)-, —NHC(O)(substituted or unsubstituted alkenylene)-,—C(O)(substituted or unsubstituted alkenylene)-, and —NHC(O)(substitutedor unsubstituted alkylene)S(substituted or unsubstitutedalkylene)C(O)NH—; and T is a mono-, bi, -or tricyclic, substituted orunsubstituted cycloalkyl, heterocyclyl, aryl, or heteroaryl.
 15. Themethod of claim 14, wherein said compound is selected from the groupconsisting of:


16. The method of claim 14, wherein T of said compound corresponds toFormula (X):

wherein A is a substituted or unsubstituted five or six-memberedheterocyclyl, aryl, or heteroaryl; and B is a substituted orunsubstituted five or six-membered heterocyclene, arylene, orheteroarylene, wherein A and B together form a fused two ring moiety.17. The method of claim 16, wherein said compound corresponds to Formula(XI):


18. The method of claim 17, wherein L of said compound is a covalentbond —C(O)NH(substituted or unsubstituted alkylene)-, —NHC(O)—,—NHC(O)(substituted or unsubstituted alkylene)-, —NH—, or —O(substitutedor unsubstituted alkylene)-.
 19. The method of claim 18, wherein saidcompound corresponds to Formula (XII):


20. The method of claim 19, wherein B of said compound is a substitutedor unsubstituted five-membered arylene or heteroarylene.
 21. The methodof claim 20, wherein said compound is:


22. The method of claim 20, wherein B is substituted or unsubstitutedthiophenylene.
 23. The method of claim 22, wherein said compound isselected from the group consisting of:


24. The method of claim 20, wherein B is substituted or unsubstitutedimidazolylene.
 25. The method of claim 24, wherein said compound isselected from the group consisting of:


26. The method of claim 20, wherein B is substituted or unsubstitutedpyrrolylene.
 27. The method of claim 26, wherein said compound isselected from the group consisting of:


28. The method of claim 19, wherein B of said compound is a substitutedor unsubstituted 6-membered arylene or heteroarylene.
 29. The method ofclaim 28, wherein B is substituted or unsubstituted phenylene.
 30. Themethod of claim 29, wherein said compound is selected from the groupconsisting of:


31. The method of claim 28, wherein B is substituted or unsubstitutedpyridinylene, pyrimidinylene, or pyridazine.
 32. The method of claim 31,wherein said compound is selected from the group consisting of:


33. The method of claim 18, wherein said compound corresponds to Formula(XIII):


34. The method of claim 33, wherein B of said compound is a substitutedor unsubstituted six-membered heteroarylene.
 35. The method of claim 34,wherein said six-membered heteroarylene is substituted or unsubstitutedpyrimidinylene.
 36. The method of claim 35, wherein said compound isselected from the group consisting of:


37. The method of claim 18, wherein L of said compound —OCR₂—.
 38. Themethod of claim 37, wherein said compound is selected from the groupconsisting of:


39. The method of claim 14, wherein L of said compound is —C(O)NH. 40.The method of claim 39, wherein said compound is selected from the groupconsisting of:


41. The method of claim 14, wherein said compound is selected from thegroup consisting of:


42. The method of claim 5, wherein said compound corresponds to Formula(XIV):

wherein: L is a linker selected from the group consisting of a covalentbond, substituted or unsubstituted alkenylene, substituted orunsubstituted alkylene, —C(O)NH—, —C(O)—, —NH—, —O—, —S—, —O(substitutedor unsubstituted alkylene)-, —N(substituted or unsubstituted alkylene)-,—C(O)NH(substituted or unsubstituted alkylene)-, —C(O)NH(substituted orunsubstituted alkenylene)- —NHC(O)(substituted or unsubstitutedalkylene)-, —NHC(O)(substituted or unsubstituted alkenylene)-,—C(O)(substituted or unsubstituted alkenylene)-, and —NHC(O)(substitutedor unsubstituted alkylene)S(substituted or unsubstitutedalkylene)C(O)NH—; and each of X₁-X₅ is independently C, CR, N, NR, S, orO, wherein no more than three of X₁-X₅ is a heteroatom, and no twoadjacent ring atoms are O or S; where each R is independently H,halogen, substituted or unsubstituted alkyl, —OR_(d), substituted orunsubstituted alkoxy, —OC(O)R_(d), —NO₂, —N(R_(d))₂, —SR_(d),—S(O)_(j)R_(d) where j is 1 or 2, —NR_(d)C(O)R_(d), —C(O)₂R_(d),—C(O)N(R_(d))₂, or —C(O)R_(d), or two adjacent R's are taken together toform a substituted or unsubstituted aryl or hetroaryl, where each R_(d)is independently H, substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl.
 43. The method of claim 42,wherein said compound corresponds to Formula (XV):


44. The method of claim 43, wherein L of said compound is a covalentbond, —C(O)NH—, or —O(substituted or unsubstituted alkylene)-.
 45. Themethod of claim 44, wherein

of said compound is selected from the group consisting of:


46. The method of claim 45, wherein said compound is selected from thegroup consisting of:


47. The method of claim 5, wherein said compound corresponds to Formula(XVI):

wherein: L is a linker selected from the group consisting of a covalentbond, substituted or unsubstituted alkenylene, substituted orunsubstituted alkylene, —C(O)NH—, —C(O)—, —NH—, —O—, —S—, —O(substitutedor unsubstituted alkylene)-, —N(substituted or unsubstituted alkylene)-,—C(O)NH(substituted or unsubstituted alkylene)-, —C(O)NH(substituted orunsubstituted alkenylene)- —NHC(O)(substituted or unsubstitutedalkylene)-, —NHC(O)(substituted or unsubstituted alkenylene)-,—C(O)(substituted or unsubstituted alkenylene)-, and —NHC(O)(substitutedor unsubstituted alkylene)S(substituted or unsubstitutedalkylene)C(O)NH—; and each of X₁-X₅ is independently C, CR, N—O, or N,wherein no more than two of X₁-X₅ is N, where each R is independently H,halogen, substituted or unsubstituted alkyl, —OR_(d), substituted orunsubstituted alkoxy, —OC(O)P_(d), —NO₂, —N(R_(d))₂, —SR_(d),—S(O)_(j)R_(d) where j is 1 or 2, —NR_(d)C(O)R_(d), —C(O)₂R_(d),—C(O)N(R_(d))₂, or —C(O)R_(d), or two adjacent R's are taken together toform a substituted or unsubstituted aryl or hetroaryl, where each R_(d)is independently H, substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl.
 48. The method of claim 47,wherein said compound corresponds to Formula (XVII):


49. The method of claim 48, wherein said compound is:


50. The method of claim 48, wherein said compound corresponds to Formula(XVIII):


51. The method of claim 50, wherein said compound is selected from thegroup consisting of:


52. The method of claim 48, wherein said compound corresponds to Formula(XXI):


53. The method of claim 52, wherein said compound is selected from thegroup consisting of:


54. The method of claim 48, wherein said compound corresponds to Formula(XXII):

wherein L is —O(substituted or unsubstituted alkylene)- or—(O)(substituted or unsubstituted alkenylene)-.
 55. The method of claim54, wherein said compound is selected from the group consisting of:


56. The method of claim 48, wherein said compound corresponds to Formula(XXIII):


57. The method of claim 56, wherein said compound is selected from thegroup consisting of:


58. The method of claim 48, wherein said compound corresponds to Formula(XXIV):


59. The method of claim 58, wherein said compound is selected from thegroup consisting of:


60. The method of claim 48, wherein said compound corresponds to Formula(XXV):


61. The method of claim 60, wherein L of said compound is —O(substitutedor unsubstituted alkylene)- or —O(substituted or unsubstitutedalkenylene)-.
 62. The method of claim 61, wherein said compound isselected from the group consisting of:


63. The method of claim 60, wherein L of said compound is —NHC(O)—. 64.The method of claim 63, wherein said compound is selected from the groupconsisting of:


65. The method of claim 60, wherein L of said compound is a covalentbond, substituted or unsubstituted alkylene, —NHC(O)(substituted orunsubstituted alkylene)-, —NHC(O)(substituted or unsubstitutedalkenylene)-, —NH(alkylene)-, —NHC(O)CH₂SCH₂C(O)NH—, and—NHC(O)(substituted alkylene)S—.
 66. The method of claim 65, whereinsaid compound is selected from the group consisting of:


67. The method of claim 10, wherein said compound corresponds to Formula(XXVI):

wherein: L is a linker selected from the group consisting of a covalentbond, substituted or unsubstituted alkenylene, substituted orunsubstituted alkylene, —C(O)NH—, —C(O)—, —NH—, —O—, —S—, —O(substitutedor unsubstituted alkylene)-, —N(substituted or unsubstituted alkylene)-,—C(O)NH(substituted or unsubstituted alkylene)-, —C(O)NH(substituted orunsubstituted alkenylene)- —NHC(O)(substituted or unsubstitutedalkylene)-, —NHC(O)(substituted or unsubstituted alkenylene)-,—C(O)(substituted or unsubstituted alkenylene)-, and —NHC(O)(substitutedor unsubstituted alkylene)S(substituted or unsubstitutedalkylene)C(O)NH—; and each of X₁-X₅ is independently C, CR, or N,wherein no more than two of X₁-X₅ is N, where each R is independently H,halogen, substituted or unsubstituted alkyl, —OH, substituted orunsubstituted alkoxy, —OC(O)R_(d), —NO₂, —N(R_(d))₂, —SR_(d),—S(O)_(j)R_(d) where j is 1 or 2, —NR_(d)C(O)R_(d), —C(O)₂R_(d),—C(O)N(R_(d))₂ or —C(O)R_(d), or two adjacent R's are taken together toform a substituted or unsubstituted aryl or hetroaryl, where each R_(d)is independently H, substituted or unsubstituted alkyl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted aryl orsubstituted or unsubstituted heteroaryl. Z₁ is O or S; and Z₂ is CR₃ orN.
 68. The method of claim 67, wherein said compound corresponds toFormula (XXVII):


69. The method of claim 68, wherein said compound is selected from thegroup consisting of:


70. The method of claim 5, wherein said compound corresponds to Formula(XVIII):

wherein: each of L and L₁ is independently a linker selected from thegroup consisting of a covalent bond, substituted or unsubstitutedalkenylene, substituted or unsubstituted alkylene, —C(O)NH—, —C(O)—,—NH—, —O—, —S—, —O(substituted or unsubstituted alkylene)-,—N(substituted or unsubstituted alkylene)-, —C(O)NH(substituted orunsubstituted alkylene), —C(O)NH(substituted or unsubstitutedalkenylene)- —NHC(O)(substituted or unsubstituted alkylene)-,—NHC(O)(substituted or unsubstituted alkenylene)-, —C(O)(substituted orunsubstituted alkenylene)-, and —NHC(O)(substituted or unsubstitutedalkylene)S(substituted or unsubstituted alkylene)C(O)NH—; U is asubstituted or unsubstituted cycloalkyl, heterocycloalkyl, aryl, orheteroaryl; and V is a substituted or unsubstituted cycloalkylene,heterocyclene, arylene, or heteroarylene.
 71. The method of claim 70,wherein said compound corresponds to Formula (XIX):


72. The method of claim 71, wherein said compound corresponds to Formula(XX):


73. The method of claim 72, wherein said compound is selected from thegroup consisting of:


74. The method of claim 71, wherein said compound corresponds to Formula(XXXI):

wherein: each of X₁-X₅ is independently C, CR, N, NR, S, or O, whereinno more than three of X₁-X₅ is a heteroatom, and no two adjacent ringatoms are O or S; and each R is independently H, halogen, substituted orunsubstituted alkyl, —OR_(d), substituted or unsubstituted alkoxy,—OC(O)R_(d), —NO₂, —N(R_(d))₂, —SR_(d), —S(O)_(j)R_(d) where j is 1 or2, —NR_(d) C(O)R_(d), —C(O)₂R_(d), —C(O)N(R_(d))₂ or —C(O)R_(d), or twoadjacent R's are taken together to form a substituted or unsubstitutedaryl or hetroaryl, where each R_(d) is independently H, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl.
 76. The method of claim 75, wherein U is a substituted orunsubstituted five-membered heteroaryl, substituted or unsubstitutedphenyl, or substituted or unsubstituted six-membered heteroaryl.
 77. Themethod of claim 76, wherein said compound is selected from the groupconsisting of:


78. The method of claim 71, wherein said compound is selected from thegroup consisting of:


79. The method of claim 4, wherein said compound corresponds to Formula(XXIII):

wherein: Z₃ is NR₃, O, or S; and Z₄ is N or CR₃.
 80. The method of claim79, wherein said compound corresponds to Formula (XXIV):


81. The method of claim 80, wherein said compound is selected from thegroup consisting of:


82. The method of claim 80, wherein said compound corresponds to Formula(XXV)

wherein: L is a linker selected from the group consisting of a covalentbond, substituted or unsubstituted alkenylene, substituted orunsubstituted alkylene, —C(O)NH—, —C(O)—, —NH—, —O—, —S—, —O(substitutedor unsubstituted alkylene)-, —N(substituted or unsubstituted alkylene)-,—C(O)NH(substituted or unsubstituted alkylene)-, —C(O)NH(substituted orunsubstituted alkenylene)- —NHC(O)(substituted or unsubstitutedalkylene)-, —NHC(O)(substituted or unsubstituted alkenylene)-,—C(O)(substituted or unsubstituted alkenylene)-, and —NHC(O)(substitutedor unsubstituted alkylene)S(substituted or unsubstitutedalkylene)C(O)NH—; and T is a substituted or unsubstituted cycloalkyl,heterocycloalkyl, aryl, or heteroaryl.
 83. The method of claim 82,wherein said compound is selected from the group consisting of:


84. The method of claim 1, wherein said compound corresponds to Formula(A):

wherein: each Z is independently C, CR₃, N, NR₃, O, or S, provided thatno more than two Z's are heteroatoms where R₃ is H, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heteroaryl, or substituted or unsubstitutedaryl. each R_(k) is independently H, halogen, substituted orunsubstituted alkyl, —OH, substituted or unsubstituted alkoxy, —OC(O)R₂,—NO₂, —N(R₂)₂, —SR₂, —C(O)R₂, —C(O)₂R₂, —C(O)N(R₂)₂, or —N(R₂)C(O)R₂,each R₂ is independently H, substituted or unsubstituted alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; or wherein two R₂ groups are linked togetherby an optionally substituted alkylene; and each R₁ is independently H,halogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, —OR_(c) —OH, —OC(O)R_(c),—NO₂, —N(R_(c))₂, —SR_(c), S(O)_(j)R_(c) where j is 1 or 2,—NR_(c)C(O)R_(c), —C(O)N(R_(c))₂, C(O)₂R_(c), or —C(O)R_(c); or twoadjacent R₁'s, are taken together to form a substituted or unsubstitutedaryl or heteroaryl, where each R_(c) is independently H, substituted orunsubstituted alkyl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted aryl, or substituted or unsubstitutedheteroaryl.
 85. The method of claim 84, wherein said compoundcorresponds to Formula (B):


86. The method of claim 84, wherein said compound is selected from thegroup consisting of:


87. The method of claim 1, wherein said compound is selected from thegroup consisting of:


88. The method of claim 1, wherein said compound is selected from thegroup consisting of:


89. A method of treating a flt-3. mediated disease, said methodcomprising administering a therapeutically effective amount of acompound corresponding to Formula (IA):

wherein: M is substituted or unsubstituted heteroaryl, or substituted orunsubstituted aryl; N is a substituted or unsubstituted aryl, orsubstituted or unsubstituted hetroaryl; and K is

Y is O or S; each R_(k) is independently H, halogen, substituted orunsubstituted alkyl, —OH, substituted or unsubstituted alkoxy, —OC(O)R₂,—NO₂, —N(R₂)₂, —SR₂, —C(O)R₂, —C(O)₂R₂, —C(O)N(R₂)₂, or —N(R₂)C(O)R₂,each R₂ is independently H, substituted or unsubstituted alkyl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aryl, or substituted orunsubstituted heteroaryl; or wherein two R₂ groups are linked togetherby an optionally substituted alkylene; and each n is independently 0, 1,2, 3 or 4; or an active metabolite, or a pharmaceutically acceptableprodrug, isomer, pharmaceutically acceptable salt or solvate thereof.